151 results on '"ANGIOTENSIN-II"'
Search Results
2. Administration of losartan preserves cardiomyocyte size and prevents myocardial dysfunction in tail-suspended mice by inhibiting p47 phox phosphorylation, NADPH oxidase activation and MuRF1 expression
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Liwen Liang, Wenyi Yuan, Lina Qu, Huili Li, Lulu Zhang, Guo-Chang Fan, and Tianqing Peng
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Angiotensin-II ,Losartan ,Microgravity ,MuRF1 ,NADPH oxidase ,p47 phox phosphorylation ,Medicine - Abstract
Abstract Background Spaceflight or microgravity conditions cause myocardial atrophy and dysfunction, contributing to post-flight orthostatic intolerance. However, the underlying mechanisms remain incompletely understood and preventive approaches are limited. This study investigated whether and how losartan, a blocker of angiotensin-II receptor, preserved cardiomyocyte size and prevented myocardial dysfunction during microgravity. Method Adult male mice were suspended with their tails to simulate microgravity. Echocardiography was performed to assess myocardial function. Heart weight and cardiomyocyte size were measured. NADPH oxidase activation was determined by analyzing membrane translocation of its cytosolic subunits including p47 phox , p67 phox and Rac1. Heart tissues were also assayed for oxidative stress, p47 phox phosphorylation (Ser345), MuRF1 protein levels and angiotensin-II production. Results Tail-suspension for 28 days increased angiotensin-II production in hearts, decreased cardiomyocyte size and heart weight, and induced myocardial dysfunction. Administration of losartan preserved cardiomyocyte size and heart weight, and prevented myocardial dysfunction in tail-suspended mice. These cardioprotective effects of losartan were associated with inhibition of p47 phox phosphorylation (Ser345), NADPH oxidase and oxidative stress in tail-suspended mouse hearts. Additionally, the NADPH oxidase inhibitor, apocynin, also reduced oxidative stress, preserved cardiomyocyte size and heart weight, and improved myocardial function in tail-suspended mice. Furthermore, losartan but not apocynin attenuated tail-suspension-induced up-regulation of MuRF1 protein in mouse hearts. Conclusions Administration of losartan preserves cardiomyocyte size and prevents myocardial dysfunction under microgravity by blocking p47 phox phosphorylation and NADPH oxidase activation, and by inhibiting MuRF1 expression. Thus, losartan may be a useful drug to prevent microgravity-induced myocardial abnormalities.
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- 2019
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3. Effect of an angiotensin-converting-enzyme inhibitor on the plasma concentration of cytokines and vasoactive molecules in patients with coronary heart disease and hypertension
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A A Khadartsev, A V Logatkina, I V Terekhov, S S Bondar, and N V Bondar
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hypertension ,angiotensin-converting enzyme inhibitor ,cytokines ,no ,angiotensin-ii ,Medicine - Abstract
Aim. To investigate the plasma concentrations of cytokines and vasoactive molecules in patients with coronary heart disease (CHD) in the presence of hypertension in relation to the angiotensin-converting-enzyme (ACE) inhibitor level reflecting the degree of renin-angiotensin-aldosterone system (RAAS) inhibition. Subjects and methods. 72 patients with NYHA functional class (FC) II-III angina pectoris and 40 healthy persons at the age of 47-65 years were examined in a controlled cohort study. Enzyme immunoassay was employed to determine the serum concentrations of interleukins (IL) (IL-2, IL-12, IL-17A, and IL-24), the vasoactive molecules of bradykinin, serotonin, ACE, angiotensin-II (AT-II), NO, and endothelin-1 (ET-1), and plasma renin activity. In addition, the plasma level of the tetrapeptide N-acetyl-Ser-Asp-Lys-Pro was used as a marker for ACE inhibition. Results. The patients with CHD occurring in the presence of hypertension compared with the apparently healthy individuals displayed decreased ET-1 and NO production along with elevated levels of serotonin, AT-II, as well as IL-17A and IL-12. The found changes were accompanied by reduced renin activity. Thus, the individuals with low ACE inhibitor levels showed more pronounced production of the proinflammatory cytokine IL-17A, as well as high plasma concentrations of ACE and NO. The high ACE inhibitor level that reflects patient adherence to appropriate antihypertensive therapy is associated with the reduced production of IL-2 and with the minimum serum levels of ACE, AT-II, and NO, being characterized by the high production of IL-12 and serotonin at the same time. Conclusion. In patients with CHD and hypertension, the high plasma enzyme inhibitor concentration that reflects the activity of appropriate antihypertensive therapy, by contributing to the strengthening of the mechanisms of relaxation of blood vessels, is associated with the risk for proinflammatory activation of whole blood cells and platelets. The mean ACE inhibitor levels that reflect moderate RAAS suppression and are characterized by a relatively low proinflammatory activation of mononuclear cells may be more preferable than the maximum ones, from the point of view of slowing the progression of the subclinical inflammatory process of the vascular wall and preventing possible CHD exacerbations. This determines the feasibility of estimating the plasma level of an ACE inhibitor to control the depth of inhibition of RAAS activity.
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- 2017
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4. Perioperative management of angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers: a survey of perioperative medicine practitioners
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Sophie L.M. Walker, Tom E.F. Abbott, Katherine Brown, Rupert M. Pearse, and Gareth L. Ackland
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Anaesthesia ,Myocardial injury ,Hypotension ,Noncardiac surgery ,Angiotensin-II ,Survey ,Medicine ,Biology (General) ,QH301-705.5 - Abstract
Background Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are the most commonly prescribed antihypertensive medications in higher-risk surgical patients. However, there is no clinical consensus on their use in the perioperative period, in part, due to an inconsistent evidence-base. To help inform the design of a large multi-centre randomized controlled trial (ISRCTN17251494), we undertook a questionnaire-based survey exploring variability in ACEi/ARB prescribing in perioperative practice. Methods The online survey included perioperative scenarios to examine how consistent respondents were with their stated routine preoperative practice. Clinicians with an academic interest in perioperative medicine were primarily targeted between July and September 2017. STROBE guidelines for observational research and ANZCA Trials Group Survey Reporting recommendations were adhered to. Results 194 responses were received, primarily from clinicians practicing in the UK. A similar minority of respondents continue ACEi (n = 57; 30%) and ARBs (n = 62; 32%) throughout the perioperative period. However, timing of preoperative cessation was highly variable, and rarely influenced by the pharmacokinetics of individual ACE-i/ARBs. Respondents’ stated routine practice was frequently misaligned with their management of common pre- and postoperative scenarios involving continuation or restarting ACE-i/ARBs. Discussion This survey highlights many inconsistencies amongst clinicians’ practice in perioperative ACE-i/ARB management. Studies designed to reveal an enhanced understanding of perioperative mechanisms at play, coupled with randomised controlled trials, are required to rationally inform the clinical management of ACE-i/ARBs in patients most at risk of postoperative morbidity.
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- 2018
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5. Cadherin-11 Deficiency Attenuates Ang-II-Induced Atrial Fibrosis and Susceptibility to Atrial Fibrillation
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Wei Cao, Yue-Peng Wang, Guojian Fang, Qun-Shan Wang, Shuai Song, and Yingze Li
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Pathology ,medicine.medical_specialty ,business.industry ,Cadherin ,Cell growth ,Immunology ,Atrial fibrillation ,medicine.disease ,Angiotensin II ,Extracellular matrix ,Pathogenesis ,atrial fibroblast ,Knockout mouse ,atrial fibrosis ,medicine ,cardiovascular system ,Immunology and Allergy ,atrial fibrillation ,cadherin-11 ,cardiovascular diseases ,business ,Journal of Inflammation Research ,Myofibroblast ,angiotensin-II ,Original Research - Abstract
Wei Cao,* Shuai Song,* Guojian Fang,* Yingze Li, Yuepeng Wang, Qun-Shan Wang Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, Peopleâs Republic of China*These authors contributed equally to this workCorrespondence: Qun-Shan Wang; Yuepeng Wang Email wangqunshan@xinhuamed.com.cn; wangyuepeng@xinhuamed.com.cnBackground: Atrial fibrosis serves as a disease initiating mechanism in the development of atrial fibrillation. Angiotensin II (Ang-II), a key mediator for atrial fibrosis, aberrantly activates atrial fibroblasts (AFs) into myofibroblasts, resulting in subsequent excessive synthesis and deposition of extracellular matrix (ECM). Cadherin-11 (CDH11) is essential in the development of non-cardiac fibrotic diseases. In this study, we investigated its role in the pathogenesis and underlying mechanism of atrial fibrillation.Methods: We obtained left atrial tissues from either patients with atrial fibrillation or Ang-II-induced atrial fibrosis mice. We utilized a global CDH11 knockout mouse (CDH11â/-) model to determine the effect of CDH11 on AF cell proliferation, migration, ECM synthesis/deposition. RNA-Seq of isolated AFs from CDH11â/- or normal mice was performed and differential expressed genes were analyzed. The mouse susceptibility to atrial fibrillation was examined by cardiac electrophysiology.Results: We found that cadherin-11 was significantly up-regulated in fibrotic atrial tissue from patients with atrial fibrillation and Ang-II-induced mice. Both normal and CDH11â/- mice did not develop atrial fibrosis at resting state. However, after Ang-II infusion, unlike severe atrial fibrosis occurred in normal mice, CDH11â/- mice displayed a reduced atrial fibrosis. Atrial fibroblasts with CDH11 deletion from CDH11â/- mice showed reduction in Ang-II-induced cell proliferation, migration and ECM synthesis/deposition, indicating the involvement of CDH11 in atrial fibrosis. Consistently, RNA-Seq of CDH11-null AFs uncovered significant decrease in pro-fibrotic gene expression. In addition, we identified reduction of transcripts associated with Smad2/3, ERK1/2 and JNK pathways. Further, CDH11â/- mice showed a significantly attenuated Ang-II-induced susceptibility to atrial fibrillation.Conclusion: Our results indicate that CDH11 potentiates Ang-II-induced activation of AFs. The pathogenesis of atrial fibrosis is through CDH11 mediated stimulation of Smad2/3, ERK1/2 and JNK pathways. Thus, CDH11 might serve as a novel therapeutic target for ameliorating the development of atrial fibrillation.Keywords: atrial fibrillation, atrial fibrosis, atrial fibroblast, cadherin-11, angiotensin-II
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- 2021
6. PU.1 inhibition attenuates atrial fibrosis and atrial fibrillation vulnerability induced by angiotensin‐II by reducing TGF‐β1/Smads pathway activation
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Lijie Yan, Jing-Jing Liu, Li Li, Shan-Ling Wang, Xian-Wei Fan, Hai-Xia Fu, Haitao Yang, Juan Hu, Lei-Ming Zhang, Jing-Jing Zhang, Jin-Tao Wu, Wei-Feng Song, Bin Kong, and Guang-Ling Hu
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Male ,0301 basic medicine ,Small interfering RNA ,Cardiotonic Agents ,angiotensin‐II ,Pharmacology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Heterocyclic Compounds ,Transforming Growth Factor beta ,In vivo ,Fibrosis ,Proto-Oncogene Proteins ,Atrial Fibrillation ,medicine ,Animals ,Smad3 Protein ,Myofibroblasts ,Transcription factor ,Cells, Cultured ,business.industry ,Angiotensin II ,Myocardium ,PU.1 ,Atrial fibrillation ,Original Articles ,Cell Biology ,medicine.disease ,Hedgehog signaling pathway ,Mice, Inbred C57BL ,030104 developmental biology ,030220 oncology & carcinogenesis ,atrial fibrosis ,Trans-Activators ,cardiovascular system ,Molecular Medicine ,Original Article ,business ,Signal Transduction ,Transforming growth factor - Abstract
Fibrosis serves a critical role in driving atrial remodelling‐mediated atrial fibrillation (AF). Abnormal levels of the transcription factor PU.1, a key regulator of fibrosis, are associated with cardiac injury and dysfunction following acute viral myocarditis. However, the role of PU.1 in atrial fibrosis and vulnerability to AF remain unclear. Here, an in vivo atrial fibrosis model was developed by the continuous infusion of C57 mice with subcutaneous Ang‐II, while the in vitro model comprised atrial fibroblasts that were isolated and cultured. The expression of PU.1 was significantly up‐regulated in the Ang‐II‐induced group compared with the sham/control group in vivo and in vitro. Moreover, protein expression along the TGF‐β1/Smads pathway and the proliferation and differentiation of atrial fibroblasts induced by Ang‐II were significantly higher in the Ang‐II‐induced group than in the sham/control group. These effects were attenuated by exposure to DB1976, a PU.1 inhibitor, both in vivo and in vitro. Importantly, in vitro treatment with small interfering RNA against Smad3 (key protein of TGF‐β1/Smads signalling pathway) diminished these Ang‐II‐mediated effects, and the si‐Smad3‐mediated effects were, in turn, antagonized by the addition of a PU.1‐overexpression adenoviral vector. Finally, PU.1 inhibition reduced the atrial fibrosis induced by Ang‐II and attenuated vulnerability to AF, at least in part through the TGF‐β1/Smads pathway. Overall, the study implicates PU.1 as a potential therapeutic target to inhibit Ang‐II‐induced atrial fibrosis and vulnerability to AF.
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- 2021
7. microRNA-29b prevents renal fibrosis by attenuating renal tubular epithelial cell–mesenchymal transition through targeting the PI3K/AKT pathway
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Hongtao Hu, Hong He, Hua Shui, Shuang Hu, and Rui Wang
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0301 basic medicine ,Nephrology ,Male ,medicine.medical_specialty ,Epithelial-Mesenchymal Transition ,Urology ,MicroRNA-29b ,Kidney ,03 medical and health sciences ,Mice ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Internal medicine ,Phosphatidylinositol 3-kinase/protein kinase B ,medicine ,Renal fibrosis ,Nephrology - Original Paper ,Animals ,Epithelial–mesenchymal transition ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cells, Cultured ,business.industry ,Akt/PKB signaling pathway ,NRK-52E cells ,Angiotensin II ,Fibrosis ,Rats ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,Kidney Tubules ,030220 oncology & carcinogenesis ,Cancer research ,Angiotensin-II ,Unilateral ureteral obstruction ,Urothelium ,business ,Proto-Oncogene Proteins c-akt - Abstract
Purpose This study aimed to investigate the effects of miR-29b on renal interstitial fibrosis in the obstructed kidney of mouse with unilateral ureteral obstruction (UUO) via inhibiting phosphatidylinositol 3-kinase/protein kinaseB (PI3K/AKT) signaling pathway. Methods Adult male CD-1 mice were intraperitoneally injected with vehicle or PI3K inhibitor LY294002 (3 mg/kg, 30 mg/kg) daily for 1 or 2 weeks after performing UUO or sham operation. The mice were sacrificed on days 7 and 14 after surgery. The rat proximal tubular epithelial cell (TEC) line NRK-52E was cultured in DMEM and treated with various concentrations angiotensin II (AngII). Obstructed and sham mouse kidneys were analyzed via HE, Masson and immunohistochemistry to assess the degree of renal fibrosis. Real-time quantitative polymerase chain reaction assays (RT-PCR) were performed to investigate changes in the levels of expression of miR-29b and Western blot was used to analyze the activation of PI3K/AKT signaling and expression of E-cadherin, α-smooth muscle actin (α-SMA). Results Histologic analyses of obstructed kidney revealed that LY294002 attenuated the degree of renal fibrosis. In this study, loss of miR-29b accompanied with increased epithelial–mesenchymal transition (EMT) was observed in renal tubules of mice after UUO and cultured NRK-52E cells exposed to AngII. LY294002 also prominently decreased phosphorylation of AKT in vivo and vitro. By RT-PCR and Western blot analysis, LY294002 blocked the PI3K/AKT-induced loss of E-cadherin expression and de novo increase of the expression of α-SMA in a time- and dose-dependent manner. The overexpression of miR-29b markedly reversed the phenotype induced by AngII in NRK-52E cells and the downregulation miR-29b expression with an miR-29b inhibitor resulted in enhanced EMT. In addition, the PI3K/AKT signaling pathway was found to be suppressed in the presence of overexpression of miR-29b by direct hybridization with 3′-untranslated region (3′-UTR) of PIK3R2. Conclusion Our findings suggested that miR-29b significantly prevented tubulointerstitial injury in mouse model of UUO by attenuating renal tubular epithelial cell–mesenchymal transition via repressing PI3K/AKT signaling pathway.
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- 2021
8. Clinical determinants and prognostic implications of renin and aldosterone in patients with symptomatic heart failure
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João Pedro Ferreira, Susan Stienen, Kenneth Dickstein, Faiez Zannad, Jozine M. ter Maaten, Chim C. Lang, Gregoire Preud'homme, Leong L. Ng, Nilesh J. Samani, Zohra Lamiral, Patrick Rossignol, Masatake Kobayashi, Adriaan A. Voors, M. Metra, Stefan D. Anker, Dirk J. van Veldhuisen, Kevin Duarte, Nicolas Girerd, Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), University Medical Center Groningen [Groningen] (UMCG), University of Bergen (UiB), Department of Cardiology, Stavanger University Hospital, Department of Cardiovascular Sciences [Leicester], University of Leicester, Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, University of Dundee, Ninewells Hospital and Medical School [Dundee], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Berlin Institute of Health Center for Regenerative Therapies, German Centre for Cardiovascular Research (DZHK) partner site Berlin, University of Brescia, Civic Hospital of Brescia, This project was funded by a grant from the European Commission (FP7-242209-BIOSTAT-CHF, EudraCT 2010–020808–29). JPF, NG, PR and FZ are supported by a public grant overseen by the French National Research Agency (ANR) as part of the second 'Investissements d’Avenir' program FIGHT-HF (reference: ANR-15-RHU-0004) and by the French PIA project 'Lorraine Université d’Excellence', reference ANR-15-IDEX-04-LUE. And by Contrat de Plan Etat-Région and FEDER Lorraine., ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), ANR-15-IDEX-0004,LUE,Isite LUE(2015), European Project: 242209,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,BIOSTAT-CHF(2010), European Project, Cardiovascular Centre (CVC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), BOZEC, Erwan, Combattre l'insuffisance cardiaque - - FIGHT-HF2015 - ANR-15-RHUS-0004 - RHUS - VALID, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure - BIOSTAT-CHF - - EC:FP7:HEALTH2010-04-01 - 2015-03-31 - 242209 - VALID, and EudraCT 2010–020808–29 - INCOMING
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medicine.medical_specialty ,lcsh:Diseases of the circulatory (Cardiovascular) system ,BASE-LINE ,Renal function ,Heart failure ,030204 cardiovascular system & hematology ,THERAPY ,DISEASE ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Mineralocorticoid receptor ,LEFT-VENTRICULAR DYSFUNCTION ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Prediction model ,Internal medicine ,Original Research Articles ,Renin–angiotensin system ,Renin ,medicine ,Humans ,030212 general & internal medicine ,Original Research Article ,Aldosterone ,Mineralocorticoid Receptor Antagonists ,PLASMA ,business.industry ,MORTALITY ,medicine.disease ,Prognosis ,Angiotensin II ,SPIRONOLACTONE ,Pathophysiology ,[SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,3. Good health ,ANGIOTENSIN-II ,ADIPOSE-TISSUE ,chemistry ,lcsh:RC666-701 ,Spironolactone ,Cardiology ,Cardiology and Cardiovascular Medicine ,business ,SYSTEM - Abstract
Aims Activation of the renin-angiotensin-aldosterone system plays an important role in the pathophysiology of heart failure (HF) and has been associated with poor prognosis. There are limited data on the associations of renin and aldosterone levels with clinical profiles, treatment response, and study outcomes in patients with HF.Methods and results We analysed 2,039 patients with available baseline renin and aldosterone levels in BIOSTAT-CHF (a systems BIOlogy study to Tailored Treatment in Chronic Heart Failure). The primary outcome was the composite of all-cause mortality or HF hospitalization. We also investigated changes in renin and aldosterone levels after administration of mineralocorticoid receptor antagonists (MRAs) in a subset of the EPHESUS trial and in an acute HF cohort (PORTO). In BIOSTAT-CHF study, median renin and aldosterone levels were 85.3 (percentile(25-75) = 28-247) mu IU/mL and 9.4 (percentile(25-75) = 4.4-19.8) ng/dL, respectively. Prior HF admission, lower blood pressure, sodium, poorer renal function, and MRA treatment were associated with higher renin and aldosterone. Higher renin was associated with an increased rate of the primary outcome [highest vs. lowest renin tertile: adjusted-HR (95% CI) = 1.47 (1.16-1.86), P = 0.002], whereas higher aldosterone was not [highest vs. lowest aldosterone tertile: adjusted-HR (95% CI) = 1.16 (0.93-1.44), P = 0.19]. Renin and/or aldosterone did not improve the BIOSTAT-CHF prognostic models. The rise in aldosterone with the use of MRAs was observed in EPHESUS and PORTO studies.Conclusions Circulating levels of renin and aldosterone were associated with both the disease severity and use of MRAs. By reflecting both the disease and its treatments, the prognostic discrimination of these biomarkers was poor. Our data suggest that the "point" measurement of renin and aldosterone in HF is of limited clinical utility.
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- 2020
9. Investigation of the Antihypertrophic and Antifibrotic Effects of Losartan in a Rat Model of Radiation-Induced Heart Disease
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Peter Horvath, Imre Földesi, Tamás Csont, Katalin Farkas, Mónika G. Kovács, Zsuzsanna Kahán, Gábor Cserni, Zsuzsanna Z. A. Kovács, Márta Sárközy, Ferenc Kovacs, Bence Kővári, Gergő Szűcs, Zoltán Varga, Marah Freiwan, Andras Kriston, and Institute for Molecular Medicine Finland
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Male ,Heart disease ,radiation-induced heart disease ,losartan ,heart failure ,Smad2 Protein ,030204 cardiovascular system & hematology ,Pharmacology ,Left ventricular hypertrophy ,THERAPY ,Rats, Sprague-Dawley ,0302 clinical medicine ,Fibrosis ,Medicine ,TGF-beta ,Biology (General) ,Spectroscopy ,Mitogen-Activated Protein Kinase 1 ,Mitogen-Activated Protein Kinase 3 ,TGF-beta/SMAD signaling pathway ,TGF-β/SMAD signaling pathway ,General Medicine ,DIASTOLIC DYSFUNCTION ,3. Good health ,Computer Science Applications ,left ventricular hypertrophy ,Chemistry ,ANGIOTENSIN-II ,Losartan ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,ALDOSTERONE ,Hypertrophy, Left Ventricular ,medicine.drug ,RADIOTHERAPY ,EXPRESSION ,onco-cardiology ,diastolic dysfunction ,fibrosis ,angiotensin-II receptor blocker (ARB) ,chymase ,QH301-705.5 ,Radiation Fibrosis Syndrome ,Connective tissue ,Article ,Catalysis ,MECHANISMS ,Transforming Growth Factor beta1 ,Inorganic Chemistry ,03 medical and health sciences ,Chymases ,Animals ,Smad3 Protein ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,Protein kinase B ,business.industry ,Organic Chemistry ,Chymase ,medicine.disease ,PREVENTION ,Rats ,HYPERTROPHY ,Disease Models, Animal ,Heart failure ,1182 Biochemistry, cell and molecular biology ,business ,DOSE-RESPONSE ,Angiotensin II Type 1 Receptor Blockers ,Proto-Oncogene Proteins c-akt - Abstract
Radiation-induced heart disease (RIHD) is a potential late side-effect of thoracic radiotherapy resulting in left ventricular hypertrophy (LVH) and fibrosis due to a complex pathomechanism leading to heart failure. Angiotensin-II receptor blockers (ARBs), including losartan, are frequently used to control heart failure of various etiologies. Preclinical evidence is lacking on the anti-remodeling effects of ARBs in RIHD, while the results of clinical studies are controversial. We aimed at investigating the effects of losartan in a rat model of RIHD. Male Sprague-Dawley rats were studied in three groups: (1) control, (2) radiotherapy (RT) only, (3) RT treated with losartan (per os 10 mg/kg/day), and were followed for 1, 3, or 15 weeks. At 15 weeks post-irradiation, losartan alleviated the echocardiographic and histological signs of LVH and fibrosis and reduced the overexpression of chymase, connective tissue growth factor, and transforming growth factor-beta in the myocardium measured by qPCR; likewise, the level of the SMAD2/3 protein determined by Western blot decreased. In both RT groups, the pro-survival phospho-AKT/AKT and the phospho-ERK1,2/ERK1,2 ratios were increased at week 15. The antiremodeling effects of losartan seem to be associated with the repression of chymase and several elements of the TGF-β/SMAD signaling pathway in our RIHD model.
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- 2021
10. A comparison between virus- versus patients-centred therapeutic attempts to reduce COVID-19 mortality
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Waly Dioh, Stanislas Veillet, René Lafont, Serge Camelo, Mathilde Latil, Pierre J. Dilda, Sam Agus, Biophytis, Sorbonne Université (SU), Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and HAL-SU, Gestionnaire
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Aging ,Epidemiology ,Mas receptor ,Anti-Inflammatory Agents ,ACE2 ,Angiotensin-Converting Enzyme Inhibitors ,Disease ,Review ,Dexamethasone ,Renin-Angiotensin System ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Discovery ,030212 general & internal medicine ,0303 health sciences ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,biology ,Mortality rate ,General Medicine ,Angiotensin-(1-7) ,Tocilizumab ,Antivirals ,3. Good health ,Infectious Diseases ,C-Reactive Protein ,Angiotensin-Converting Enzyme 2 ,Viral load ,medicine.drug ,medicine.medical_specialty ,Immunology ,Remdesivir ,Microbiology ,Antiviral Agents ,03 medical and health sciences ,Virology ,medicine ,Humans ,Intensive care medicine ,Emerging and Re-Emerging Coronaviruses ,030304 developmental biology ,IL-6 ,business.industry ,SARS-CoV-2 ,C-reactive protein ,COVID-19 ,Angiotensin II ,COVID-19 Drug Treatment ,chemistry ,Respiratory failure ,biology.protein ,Angiotensin-II ,Parasitology ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; Since December 2019, coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has changed our lives. Elderly, and those with comorbidities represent the vast majority of patients hospitalized with severe COVID-19 symptoms, including acute respiratory disease syndrome, and cardiac dysfunction. Despite a huge effort of the scientific community, improved treatment modalities limiting the severity and mortality of hospitalized COVID-19 patients, are still required. Here, we compare the effectiveness of virus- and patients-centred strategies to reduce COVID-19 mortality. We also discuss the therapeutic options that might further reduce death rates associated with the disease in the future. Unexpectedly, extensive review of the literature suggests that SARS-CoV-2 viral load seems to be associated neither with the severity of symptoms nor with mortality of hospitalized patients with COVID-19. This may explain why, so far, virus-centred strategies using antivirals aiming to inhibit the viral replicative machinery, have failed to reduce COVID-19 mortality in patients with respiratory failure. By contrast, anti-inflammatory treatments without antiviral capacities but centred on patients, such as dexamethasone or Tocilizumab®, reduce COVID-19 mortality. Finally, since the spike protein of SARS-CoV-2 binds to Angiotensin Converting Enzyme 2 (ACE2) and inhibits its function, we explore the different treatment options focussing on rebalancing the Renin-Angiotensin System (RAS). This new therapeutic strategy could hopefully further reduce the severity of respiratory failure and limit COVID-19 mortality in elderly patients.
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- 2021
11. Aquaporin 2 regulation:implications for water balance and polycystic kidney diseases
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Emma T. B. Olesen and Robert A. Fenton
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0301 basic medicine ,CYST GROWTH ,030232 urology & nephrology ,Autosomal dominant polycystic kidney disease ,CYCLIC-AMP ,urologic and male genital diseases ,03 medical and health sciences ,0302 clinical medicine ,Arginine vasopressin receptor 2 ,Polycystic kidney disease ,Medicine ,Protein kinase A ,Receptor ,DEPENDENT PROTEIN-KINASE ,F-ACTIN ,business.industry ,urogenital system ,MOLECULAR-MECHANISMS ,APICAL MEMBRANE ,medicine.disease ,Cell biology ,ANGIOTENSIN-II ,030104 developmental biology ,Nephrology ,Aquaporin 2 ,Knockout mouse ,DIABETES-INSIPIDUS ,VASOPRESSIN-MEDIATED TRANSLOCATION ,THICK ASCENDING LIMB ,business ,Homeostasis - Abstract
Targeting the collecting duct water channel aquaporin 2 (AQP2) to the plasma membrane is essential for the maintenance of mammalian water homeostasis. The vasopressin V2 receptor (V2R), which is a GS protein-coupled receptor that increases intracellular cAMP levels, has a major role in this targeting process. Although a rise in cAMP levels and activation of protein kinase A are involved in facilitating the actions of V2R, studies in knockout mice and cell models have suggested that cAMP signalling pathways are not an absolute requirement for V2R-mediated AQP2 trafficking to the plasma membrane. In addition, although AQP2 phosphorylation is a known prerequisite for V2R-mediated plasma membrane targeting, none of the known AQP2 phosphorylation events appears to be rate-limiting in this process, which suggests the involvement of other factors; cytoskeletal remodelling has also been implicated. Notably, several regulatory processes and signalling pathways involved in AQP2 trafficking also have a role in the pathophysiology of autosomal dominant polycystic kidney disease, although the role of AQP2 in cyst progression is unknown. Here, we highlight advances in the field of AQP2 regulation that might be exploited for the treatment of water balance disorders and provide a rationale for targeting these pathways in autosomal dominant polycystic kidney disease.
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- 2021
12. Novel Ratio Soluble Fms-like Tyrosine Kinase-1/Angiotensin-II (sFlt-1/ANG-II) in Pregnant Women Is Associated with Critical Illness in COVID-19
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Iris Paola Guzmán-Guzmán, Lourdes Rojas-Zepeda, Liona C. Poon, Raigam Jafet Martinez-Portilla, Jose Antonio Hernandez-Pacheco, Salvador Espino-Y-Sosa, Paloma Mateu-Rogell, Aurora Espejel-Nuñez, Guadalupe Estrada-Gutierrez, J. Torres-Torres, Angeles Juarez-Reyes, Francisco Eduardo Lopez-Ceh, José Rafael Villafán-Bernal, and Juan Mario Solis-Paredes
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Adult ,medicine.medical_specialty ,Critical Illness ,Placenta ,angiogenic factors ,sFlt-1 ,Gastroenterology ,Microbiology ,endothelial dysfunction ,Cohort Studies ,Sepsis ,Pre-Eclampsia ,Pregnancy ,Virology ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Adverse effect ,Prospective cohort study ,Mexico ,angiotensin-II ,Vascular Endothelial Growth Factor Receptor-1 ,business.industry ,SARS-CoV-2 ,Angiotensin II ,Communication ,Brief Report ,COVID-19 ,Odds ratio ,medicine.disease ,QR1-502 ,Pneumonia ,Infectious Diseases ,maternal death ,embryonic structures ,Maternal death ,Female ,Pregnant Women ,business ,Soluble fms-like tyrosine kinase-1 ,Biomarkers - Abstract
Background: In healthy pregnancies, components of the Renin-Angiotensin system (RAS) are present in the placental villi and contribute to invasion, migration, and angiogenesis. At the same time, soluble fms-like tyrosine kinase 1 (sFlt-1) production is induced after binding of ANG-II to its receptor (AT-1R) in response to hypoxia. As RAS plays an essential role in the pathogenesis of COVID-19, we hypothesized that angiogenic marker (sFlt-1) and RAS components (ANG-II and ACE-2) may be related to adverse outcomes in pregnant women with COVID-19; Methods: Prospective cohort study. Primary outcome was severe pneumonia. Secondary outcomes were ICU admission, intubation, sepsis, and death. Spearman’s Rho test was used to analyze the correlation between sFlt-1 and ANG-II levels. The sFlt-1/ANG-II ratio was determined and the association with each adverse outcome was explored by logistic regression analysis and the prediction was assessed using receiver-operating-curve (ROC); Results: Among 80 pregnant women with COVID-19, the sFlt-1/ANG-II ratio was associated with an increased probability of severe pneumonia (odds ratio [OR]: 1.31; p = 0.003), ICU admission (OR: 1.05; p = 0.007); intubation (OR: 1.09; p = 0.008); sepsis (OR: 1.04; p = 0.008); and death (OR: 1.04; p = 0.018); Conclusion: sFlt-1/ANG-II ratio is a good predictor of adverse events such as pneumonia, ICU admission, intubation, sepsis, and death in pregnant women with COVID-19.
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- 2021
13. Excessive adventitial stress drives inflammation-mediated fibrosis in hypertensive aortic remodelling in mice
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Mo Wang, Chang-Shun He, Bart Spronck, George Tellides, Alexia Rojas, Matthew R. Bersi, Bo Jiang, Marcos Latorre, Sameet Mehta, Abhay B. Ramachandra, Alexander W. Caulk, Sae-Il Murtada, Pengwei Ren, Jay D. Humphrey, Biomedische Technologie, and RS: Carim - H07 Cardiovascular System Dynamics
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0301 basic medicine ,INVOLVEMENT ,C57BL/6 J ,Pathology ,VASCULAR WALL ,SMOOTH-MUSCLE-CELLS ,Aorta, Thoracic ,030204 cardiovascular system & hematology ,Biochemistry ,Muscle, Smooth, Vascular ,Muscle hypertrophy ,ACTIVATION ,Mice ,stiffness ,0302 clinical medicine ,Fibrosis ,03.- Garantizar una vida saludable y promover el bienestar para todos y todas en todas las edades ,COLLAGEN-SYNTHESIS ,smooth muscle phenotype ,129S6 ,129S6/SvEvTac ,SvEvTac ,ANGIOTENSIN-II ,medicine.anatomical_structure ,Hypertension ,medicine.symptom ,Biotechnology ,Adventitia ,medicine.medical_specialty ,Biomedical Engineering ,Biophysics ,Bioengineering ,Inflammation ,contractility ,Article ,Biomaterials ,03 medical and health sciences ,6 J ,medicine.artery ,medicine ,Animals ,ACCUMULATION ,ARTERIAL ADAPTATIONS ,Aorta ,business.industry ,fibrosis ,medicine.disease ,Angiotensin II ,Mice, Inbred C57BL ,HYPERTROPHY ,Disease Models, Animal ,aorta ,C57BL ,030104 developmental biology ,inflammation ,AT(1) RECEPTOR ,business ,Vasoconstriction ,Homeostasis - Abstract
[EN] Hypertension induces significant aortic remodelling, often adaptive but sometimes not. To identify immuno-mechanical mechanisms responsible for differential remodelling, we studied thoracic aortas from 129S6/SvEvTac and C57BL/6 J mice before and after continuous 14-day angiotensin II infusion, which elevated blood pressure similarly in both strains. Histological and biomechanical assessments of excised vessels were similar at baseline, suggesting a common homeostatic set-point for mean wall stress. Histology further revealed near mechano-adaptive remodelling of the hypertensive 129S6/SvEvTac aortas, but a grossly maladaptive remodelling of C57BL/6 J aortas. Bulk RNA sequencing suggested that increased smooth muscle contractile processes promoted mechano-adaptation of 129S6/SvEvTac aortas while immune processes prevented adaptation of C57BL/6 J aortas. Functional studies confirmed an increased vasoconstrictive capacity of the former while immunohistochemistry demonstrated marked increases in inflammatory cells in the latter. We then used multiple computational biomechanical models to test the hypothesis that excessive adventitial wall stress correlates with inflammatory cell infiltration. These models consistently predicted that increased vasoconstriction against an increased pressure coupled with modest deposition of new matrix thickens the wall appropriately, restoring wall stress towards homeostatic consistent with adaptive remodelling. By contrast, insufficient vasoconstriction permits high wall stresses and exuberant inflammation-driven matrix deposition, especially in the adventitia, reflecting compromised homeostasis and gross maladaptation., This work was supported by grants from NIH (grant nos. R01HL105297, P01 HL134605, U01 HL142518, R01 HL146723), Netherlands Organisation for Scientific Research (grant no. Rubicon 452172006) and the European Union¿s Horizon 2020 research and innovation program (grant no. 793805)
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- 2021
14. The Ca2+-activated cation channel TRPM4 is a positive regulator of pressure overload-induced cardiac hypertrophy
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Robert M. Graham, Boris Martinac, Charles D. Cox, Yang Guo, Ze-Yan Yu, Andrea Y. Chan, Sara R. Holman, Siiri E. Iismaa, Silvia Pinto, Scott H. Kesteven, Jianxin Wu, Rudi Vennekens, Hutao Gong, Michael P. Feneley, and Andy Pironet
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0301 basic medicine ,Life Sciences & Biomedicine - Other Topics ,EXPRESSION ,medicine.medical_specialty ,QH301-705.5 ,Science ,Regulator ,030204 cardiovascular system & hematology ,Left ventricular hypertrophy ,General Biochemistry, Genetics and Molecular Biology ,CARDIOMYOCYTES ,CALCINEURIN ,mechanosensitive channels ,SIGNALING PATHWAYS ,03 medical and health sciences ,Transient receptor potential channel ,CAM KINASE-II ,0302 clinical medicine ,cardiovascular disease ,Internal medicine ,Medicine ,cardiovascular diseases ,Biology (General) ,CALMODULIN ,Biology ,Pressure overload ,Science & Technology ,General Immunology and Microbiology ,RECEPTOR ,business.industry ,General Neuroscience ,General Medicine ,medicine.disease ,Hedgehog signaling pathway ,left ventricular hypertrophy ,ANGIOTENSIN-II ,030104 developmental biology ,Chemical signal ,Cardiac hypertrophy ,Cardiology ,HEART-FAILURE ,Mechanosensitive channels ,Ca2+/calmodulin-dependent protein kinase II ,SENSITIVITY ,business ,Life Sciences & Biomedicine - Abstract
Pathological left ventricular hypertrophy (LVH) occurs in response to pressure overload and remains the single most important clinical predictor of cardiac mortality. The molecular pathways in the induction of pressure overload LVH are potential targets for therapeutic intervention. Current treatments aim to remove the pressure overload stimulus for LVH, but do not completely reverse adverse cardiac remodelling. Although numerous molecular signalling steps in the induction of LVH have been identified, the initial step by which mechanical stretch associated with cardiac pressure overload is converted into a chemical signal that initiates hypertrophic signalling remains unresolved. In this study, we show that selective deletion of transient receptor potential melastatin 4 (TRPM4) channels in mouse cardiomyocytes results in an approximately 50% reduction in the LVH induced by transverse aortic constriction. Our results suggest that TRPM4 channel is an important component of the mechanosensory signalling pathway that induces LVH in response to pressure overload and represents a potential novel therapeutic target for the prevention of pathological LVH. ispartof: ELIFE vol:10 ispartof: location:England status: published
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- 2021
15. Administration of losartan preserves cardiomyocyte size and prevents myocardial dysfunction in tail-suspended mice by inhibiting p47 phox phosphorylation, NADPH oxidase activation and MuRF1 expression
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Huili Li, Wenyi Yuan, Lulu Zhang, Guo-Chang Fan, Liwen Liang, Lina Qu, and Peng Tianqing
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Male ,0301 basic medicine ,Muscle Proteins ,lcsh:Medicine ,Blood Pressure ,medicine.disease_cause ,Tripartite Motif Proteins ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Diastole ,Myocytes, Cardiac ,Phosphorylation ,Receptor ,Apelin Receptors ,NADPH oxidase ,biology ,Angiotensin II ,Organ Size ,General Medicine ,MuRF1 ,Losartan ,Hindlimb Suspension ,030220 oncology & carcinogenesis ,Apelin ,Valsartan ,medicine.drug ,medicine.medical_specialty ,p47phox phosphorylation ,Ubiquitin-Protein Ligases ,RAC1 ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,Cell Size ,Myocardium ,Research ,lcsh:R ,DNA Helicases ,Enzyme Activation ,030104 developmental biology ,Endocrinology ,chemistry ,Oxidative stress ,Apocynin ,biology.protein ,Angiotensin-II ,ATPases Associated with Diverse Cellular Activities ,Microgravity ,p47 phox phosphorylation - Abstract
Background Spaceflight or microgravity conditions cause myocardial atrophy and dysfunction, contributing to post-flight orthostatic intolerance. However, the underlying mechanisms remain incompletely understood and preventive approaches are limited. This study investigated whether and how losartan, a blocker of angiotensin-II receptor, preserved cardiomyocyte size and prevented myocardial dysfunction during microgravity. Method Adult male mice were suspended with their tails to simulate microgravity. Echocardiography was performed to assess myocardial function. Heart weight and cardiomyocyte size were measured. NADPH oxidase activation was determined by analyzing membrane translocation of its cytosolic subunits including p47 phox , p67 phox and Rac1. Heart tissues were also assayed for oxidative stress, p47 phox phosphorylation (Ser345), MuRF1 protein levels and angiotensin-II production. Results Tail-suspension for 28 days increased angiotensin-II production in hearts, decreased cardiomyocyte size and heart weight, and induced myocardial dysfunction. Administration of losartan preserved cardiomyocyte size and heart weight, and prevented myocardial dysfunction in tail-suspended mice. These cardioprotective effects of losartan were associated with inhibition of p47 phox phosphorylation (Ser345), NADPH oxidase and oxidative stress in tail-suspended mouse hearts. Additionally, the NADPH oxidase inhibitor, apocynin, also reduced oxidative stress, preserved cardiomyocyte size and heart weight, and improved myocardial function in tail-suspended mice. Furthermore, losartan but not apocynin attenuated tail-suspension-induced up-regulation of MuRF1 protein in mouse hearts. Conclusions Administration of losartan preserves cardiomyocyte size and prevents myocardial dysfunction under microgravity by blocking p47 phox phosphorylation and NADPH oxidase activation, and by inhibiting MuRF1 expression. Thus, losartan may be a useful drug to prevent microgravity-induced myocardial abnormalities.
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- 2019
16. アンジオテンシンII 受容体拮抗薬であるロサルタンは、レンバチニブによるヒト肝癌細胞への 細胞増殖抑制性および血管新生抑制効果の感性を向上させる
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Hirotetsu Takagi, Kosuke Kaji, Akira Mitoro, Takemi Akahane, Hiroaki Takaya, Kei Moriya, Hitoshi Yoshiji, Koji Ishida, Norihisa Nishimura, Tadashi Namisaki, Hiroyuki Ogawa, and Hideto Kawaratani
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Angiotensin receptor ,Angiogenesis ,medicine.medical_treatment ,lenvatinib ,Article ,Losartan ,Targeted therapy ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,angiogenesis ,0302 clinical medicine ,Animals ,Humans ,Medicine ,HCC ,Autocrine signalling ,lcsh:QH301-705.5 ,angiotensin-II ,business.industry ,Cell growth ,Phenylurea Compounds ,Liver Neoplasms ,General Medicine ,Cytostatic Agents ,Angiotensin II ,VEGF ,chemistry ,lcsh:Biology (General) ,030220 oncology & carcinogenesis ,Quinolines ,Cancer research ,030211 gastroenterology & hepatology ,Lenvatinib ,business ,Angiotensin II Type 1 Receptor Blockers ,medicine.drug - Abstract
Molecular targeted therapy with lenvatinib is commonly offered to advanced hepatocellular carcinoma (HCC) patients, although it is often interrupted by adverse effects which require a reduction in the initial dose. Thus, an alternative lenvatinib-based therapy to compensate for dose reduction is anticipated. This study aimed to assess the effect of combination of low-dose of lenvatinib and the angiotensin-II (AT-II) receptor blocker losartan on human HCC cell growth. In vitro studies found that losartan suppressed the proliferation by inducing G1 arrest and caused apoptosis as indicated by the cleavage of caspase-3 in AT-II-stimulated HCC cell lines (Huh-7, HLE, and JHH-6). Losartan attenuated the AT-II-stimulated production of vascular endothelial growth factor-A (VEGF-A) and interleukin-8 and suppressed lenvatinib-mediated autocrine VEGF-A production in HCC cells. Moreover, it directly inhibited VEGF-mediated endothelial cell growth. Notably, the combination of lenvatinib and losartan augmented the cytostatic and angiostatic effects of the former at a low-dose, reaching those achieved with a conventional dose. Correspondingly, a HCC tumor xenograft assay showed that the oral administration of losartan combined with lenvatinib reduced the subcutaneous tumor burden and intratumor vascularization in BALB/c nude mice. These findings support that this regimen could be a viable option for patients intolerant to standard lenvatinib dosage., 博士(医学)・甲第813号・令和4年3月15日, © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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- 2021
17. Complementary roles of mechanotransduction and inflammation in vascular homeostasis
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Jay D. Humphrey, Bart Spronck, Marcos Latorre, Biomedische Technologie, and RS: Carim - H07 Cardiovascular System Dynamics
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Vascular homeostasis ,Mechanotransduction ,General Mathematics ,SMOOTH-MUSCLE-CELLS ,Pulsatile flow ,General Physics and Astronomy ,Inflammation ,030204 cardiovascular system & hematology ,Biology ,ACTIVATION ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Homeostasis ,03.- Garantizar una vida saludable y promover el bienestar para todos y todas en todas las edades ,COLLAGEN-SYNTHESIS ,MACROPHAGES ,AORTIC ADVENTITIAL FIBROBLASTS ,030304 developmental biology ,0303 health sciences ,RECEPTOR ,General Engineering ,WALL ,Angiotensin II ,Artery ,Cell biology ,ANGIOTENSIN-II ,medicine.anatomical_structure ,TISSUE ,Hypertension ,medicine.symptom ,Research Article - Abstract
[EN] Arteries are exposed to relentless pulsatile haemodynamic loads, but via mechanical homeostasis they tend to maintain near optimal structure, properties and function over long periods in maturity in health. Numerous insults can compromise such homeostatic tendencies, however, resulting in maladaptations or disease. Chronic inflammation can be counted among the detrimental insults experienced by arteries, yet inflammation can also play important homeostatic roles. In this paper, we present a new theoretical model of complementary mechanobiological and immunobiological control of vascular geometry and composition, and thus properties and function. We motivate and illustrate the model using data for aortic remodelling in a common mouse model of induced hypertension. Predictions match the available data well, noting a need for increased data for further parameter refinement. The overall approach and conclusions are general, however, and help to unify two previously disparate literatures, thus leading to deeper insight into the separate and overlapping roles of mechanobiology and immunobiology in vascular health and disease., This work was supported, in part, by grants from the US National Institutes of Health (grant nos. R01 HL105297, P01 HL134605, R01 HL146723)
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- 2021
18. Does Angiotensin II Peak in Response to SARS-CoV-2?
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Léder Leal Xavier, Luis Fernando Saraiva Macedo Timmers, Lisiê Valéria Paz, Paula Fernanda Ribas Neves, Laura Tartari Neves, Alberto A. Rasia-Filho, Pamela Brambilla Bagatini, Régis Gemerasca Mestriner, and Andrea Wieck
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lcsh:Immunologic diseases. Allergy ,0301 basic medicine ,Immunology ,Disease ,030204 cardiovascular system & hematology ,immune activation ,immune response ,Renin-Angiotensin System ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Immunity ,Renin–angiotensin system ,Humans ,Immunology and Allergy ,Medicine ,Receptor ,angiotensin-II ,SARS-CoV-2 ,business.industry ,Angiotensin II ,COVID-19 ,Angiotensin-converting enzyme 2 ,Pathophysiology ,030104 developmental biology ,Host-Pathogen Interactions ,Perspective ,lcsh:RC581-607 ,business - Abstract
Human infection by the SARS-CoV-2 is causing the current COVID-19 pandemic. With the growing numbers of cases and deaths, there is an urgent need to explore pathophysiological hypotheses in an attempt to better understand the factors determining the course of the disease. Here, we hypothesize that COVID-19 severity and its symptoms could be related to transmembrane and soluble Angiotensin-converting enzyme 2 (tACE2 and sACE2); Angiotensin II (ANG II); Angiotensin 1-7 (ANG 1-7) and angiotensin receptor 1 (AT1R) activation levels. Additionally, we hypothesize that an early peak in ANG II and ADAM-17 might represent a physiological attempt to reduce viral infection via tACE2. This viewpoint presents: (1) a brief introduction regarding the renin-angiotensin-aldosterone system (RAAS), detailing its receptors, molecular synthesis, and degradation routes; (2) a description of the proposed early changes in the RAAS in response to SARS-CoV-2 infection, including biological scenarios for the best and worst prognoses; and (3) the physiological pathways and reasoning for changes in the RAAS following SARS-CoV-2 infection.
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- 2021
19. Nanoparticles Mimicking Viral Cell Recognition Strategies Are Superior Transporters into Mesangial Cells
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Achim Goepferich, Philipp Tauber, Sara Maslanka Figueroa, Frank Schweda, Ralph Witzgall, Sebastian Beck, and Daniel Fleischmann
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mesangial cells ,General Chemical Engineering ,ANGIOTENSIN-II ,GLOMERULAR MESANGIUM ,POLYETHYLENE-GLYCOL ,DRUG-DELIVERY ,RECEPTOR ,VIRUS ,BINDING ,AT(1) ,INTERNALIZATION ,TRAFFICKING ,multivalent nanoparticles ,renal targeting ,stepwise cell recognition ,virus-mimetic ,Cell ,General Physics and Astronomy ,Medicine (miscellaneous) ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Pharmacotherapy ,615 Pharmazie ,In vivo ,medicine ,570 Biowissenschaften, Biologie ,General Materials Science ,lcsh:Science ,Kidney ,Full Paper ,Chemistry ,virus‐mimetic ,General Engineering ,Transporter ,Full Papers ,021001 nanoscience & nanotechnology ,ddc:615 ,0104 chemical sciences ,Cell biology ,medicine.anatomical_structure ,Mesangium ,Nucleic acid ,lcsh:Q ,ddc:570 ,Nanocarriers ,0210 nano-technology - Abstract
Poor drug availability in the tissue of interest is a frequent cause of therapy failure. While nanotechnology has developed a plethora of nanocarriers for drug transport, their ability to unequivocally identify cells of interest remains moderate. Viruses are the ideal nanosized carriers as they are able to address their embedded nucleic acids with high specificity to their host cells. Here, it is reported that particles endowed with a virus‐like ability to identify cells by three consecutive checks have a superior ability to recognize mesangial cells (MCs) in vivo compared to conventional nanoparticles. Mimicking the initial viral attachment followed by a stepwise target cell recognition process leads to a 5‐ to 15‐fold higher accumulation in the kidney mesangium and extensive cell uptake compared to particles lacking one or both of the viral traits. These results highlight the relevance that the viral cell identification process has on specificity and its application on the targeting strategies of nanomaterials. More so, these findings pave the way for transporting drugs into the mesangium, a tissue that is pivotal in the development of diabetic nephropathy and for which currently no efficient pharmacotherapy exists., Nanoparticles (NPs) endowed with viral targeting strategies are presented. A triple‐check for cell identity is implemented by mimicking the initial viral cell attachment, followed by a stepwise enzyme‐activated recognition and internalization. Particles with these viral attributes are able to accumulate in mesangial cells, a therapeutic target of paramount importance due to their involvement in kidney diseases, such as diabetic nephropathy.
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- 2020
20. Right atrial myocardial remodeling in children with atrial septal defect involves inflammation, growth, fibrosis and apoptosis
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Jaime F. Vazquez-Jimenez, Marie-Christine Seghaye, Ruth Heying, Nesrine Farhat, Hatem Rouatbi, and Arlette Gerard
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EXPRESSION ,CARDIOTROPHIN-1 ,Pathology ,medicine.medical_specialty ,Programmed cell death ,Angiogenesis ,growth ,Volume overload ,myocardial remodeling ,INFANTS ,Inflammation ,030204 cardiovascular system & hematology ,Pediatrics ,atrial septum defect ,ACTIVATION ,03 medical and health sciences ,0302 clinical medicine ,Fibrosis ,030225 pediatrics ,medicine ,Original Research ,IL-6 ,TUNEL assay ,Science & Technology ,business.industry ,fibrosis ,CYTOKINES ,lcsh:RJ1-570 ,apoptosis ,lcsh:Pediatrics ,CARDIOMYOCYTE APOPTOSIS ,CARDIAC FIBROBLASTS ,medicine.disease ,congenital heart disease ,ANGIOTENSIN-II ,Apoptosis ,inflammation ,Pediatrics, Perinatology and Child Health ,Immunohistochemistry ,medicine.symptom ,business ,INFARCTION ,Life Sciences & Biomedicine - Abstract
Introduction: Myocardial remodeling due to large atrial septum defect (ASD) is macroscopically characterized by dilation of the right-sided cardiac cavities secondary to volume overload, the cellular mechanisms of which are not yet understood. We postulated that inflammation, fibrosis, and cell death are actors of right atrial remodeling secondary to ASD. Patients and Methods: In 12 children with large ASD (median age: 63 months), expression of genes coding for proteins involved in the response to cell stress and -protection, inflammation, growth and angiogenesis, fibrosis, and apoptosis was assessed by RT-PCR in right atrial myocardial biopsies taken during cardiac surgery. The presence of cytokines in myocardial cells was confirmed by immunohistochemistry and effective apoptosis by TUNEL assay. Results: In all patients investigated, a cellular response to early mechanical stress with the initiation of early protective mechanisms, of inflammation (and its control), -growth, and -angiogenesis, of fibrosis and apoptosis was present. The apoptotic index assessed by TUNEL assay averaged 0.3%. Conclusions: In children with large ASD, macroscopic right atrial remodeling relates to cellular mechanisms involving the expression of numerous genes that either still act to protect cells and tissues but that also harm as they initiate and/or sustain inflammation, fibrosis, and cell death by apoptosis. This may contribute to long term morbidity in patients with ASD. ispartof: Frontiers In Pediatrics vol:8 ispartof: location:Switzerland status: published
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- 2020
21. Cyp2j5-Gene Deletion Affects on Acetylcholine and Adenosine-Induced Relaxation in Mice: Role of Angiotensin-II and CYP-Epoxygenase Inhibitor
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Mohammed A. Nayeem, Darryl C. Zeldin, Stephanie O. Agba, Matthew L Edin, and Ahmad Hanif
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0301 basic medicine ,medicine.medical_specialty ,Adenosine A2A receptor ,Nitric oxide ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,relaxation ,Internal medicine ,medicine ,Pharmacology (medical) ,Reactive hyperemia ,angiotensin-II ,Original Research ,CYP-epoxygenases ,Pharmacology ,adenosine A2A receptor ,lcsh:RM1-950 ,Angiotensin II ,Adenosine ,acetylcholine ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,Endocrinology ,chemistry ,adenosine ,030220 oncology & carcinogenesis ,Knockout mouse ,cardiovascular system ,medicine.symptom ,Vasoconstriction ,Acetylcholine ,medicine.drug - Abstract
Previously, we showed vascular endothelial overexpression of human-CYP2J2 enhances coronary reactive hyperemia in Tie2-CYP2J2 Tr mice, and eNOS−/− mice had overexpression of CYP2J-epoxygenase with adenosine A2A receptor-induced enhance relaxation, but we did not see the response in CYP2J-epoxygenase knockout mice. Therefore, we hypothesized that Cyp2j5-gene deletion affects acetylcholine- and 5'-N-ethylcarboxamidoadenosine (NECA) (adenosine)-induced relaxation and their response is partially inhibited by angiotensin-II (Ang-II) in mice. Acetylcholine (Ach)-induced response was tested with N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH, CYP-epoxygenase inhibitor; 10−5M) and Ang-II (10−6M). In Cyp2j5−/− mice, ACh-induced relaxation was different from C57Bl/6 mice, at 10−5 M (76.1 ± 3.3 vs. 58.3 ± 5.2, P < 0.05). However, ACh-induced relaxation was not blocked by MS-PPOH in Cyp2j5−/−: 58.5 ± 5.0%, P > 0.05, but blocked in C57Bl/6: 52.3 ± 7.5%, P < 0.05, and Ang-II reduces ACh-induced relaxation in both Cyp2j5−/− and C57Bl/6 mice (38.8 ± 3.9% and 45.9 ± 7.8, P 0.05). However, NECA-induced response was reduced by Ang-II in both Cyp2j5−/− and C57Bl/6 mice (−10.8 ± 2.3% and 3.2 ± 2.7, P < 0.05). Data suggest that ACh-induced relaxation in Cyp2j5−/− mice depends on nitric oxide (NO) but not CYP-epoxygenases, and the NECA-induced different response in male vs. female Cyp2j5−/− mice when Ang-II treated.
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- 2020
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22. MicroRNAs in Chronic Kidney Disease: Four Candidates for Clinical Application
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Emiel P. C. van der Vorst, Juergen Floege, Linsey J. F. Peters, Joachim Jankowski, and Erik A.L. Biessen
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0301 basic medicine ,DOWN-REGULATION ,HIGH GLUCOSE ,030232 urology & nephrology ,kidney fibrosis ,Review ,Kidney ,Bioinformatics ,Pathogenesis ,Diabetic nephropathy ,lcsh:Chemistry ,0302 clinical medicine ,Medicine ,lcsh:QH301-705.5 ,Spectroscopy ,Glomerulonephritis ,General Medicine ,MOUSE MODEL ,Computer Science Applications ,clinical application ,ANGIOTENSIN-II ,medicine.anatomical_structure ,PROMOTES RENAL FIBROSIS ,Catalysis ,DIABETIC-NEPHROPATHY ,Inorganic Chemistry ,03 medical and health sciences ,Hypertensive Nephropathy ,microRNA ,Humans ,Renal Insufficiency, Chronic ,Physical and Theoretical Chemistry ,Molecular Biology ,AKT KINASE ,MESENCHYMAL TRANSITION ,business.industry ,Organic Chemistry ,COLLAGEN EXPRESSION ,medicine.disease ,MicroRNAs ,030104 developmental biology ,Gene Expression Regulation ,lcsh:Biology (General) ,lcsh:QD1-999 ,Tubulointerstitial fibrosis ,business ,chronic kidney disease ,CARDIORENAL SYNDROME ,Kidney disease - Abstract
International journal of molecular sciences 21(18), 6547 (2020). doi:10.3390/ijms21186547 special issue: "Special Issue "The Role of Non-coding RNAs in Kidney Diseases" / Special Issue Editors: Prof. Dr. Laurent Metzinger, Guest Editor; Dr. Juan Antonio Moreno, Guest Editor; Dr. Valérie Metzinger-Le Meuth, Guest Editor", Published by Molecular Diversity Preservation International, Basel
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- 2020
23. Plasma Renin Measurements are Unrelated to Mineralocorticoid Replacement Dose in Patients With Primary Adrenal Insufficiency
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Salma R Ali, Ruth Krone, Vivien Thornton-Jones, Feyza Darendeliler, Mirela C Miranda, Violeta Iotova, Tulay Guran, Jillian Bryce, Nils Krone, S Faisal Ahmed, Walter Bonfig, Antonio Balsamo, Amalia Cannuccia, Claire E Higham, Richard J. Ross, Wiebke Arlt, Andrea M. Isidori, Jeremy W. Tomlinson, Ayla Güven, Tania A. S. S. Bachega, Federico Baronio, Márta Korbonits, Berenice B. Mendonca, Riccardo Pofi, Liat de Vries, Alessandro Prete, Andrea Lenzi, Pofi, Riccardo, Prete, Alessandro, Thornton-Jones, Vivien, Bryce, Jillian, Ali, Salma R., Ahmed, S. Faisal, Balsamo, Antonio, Baronio, Federico, Cannuccia, Amalia, Guven, Ayla, Guran, Tulay, Darendeliler, Feyza, Higham, Claire, Bonfig, Walter, de Vries, Liat, Bachega, Tania A. S. S., Miranda, Mirela C., Mendonca, Berenice B., Iotova, Violeta, Korbonits, Marta, Krone, Nils P., Krone, Ruth, Lenzi, Andrea, Arlt, Wiebke, Ross, Richard J., Isidori, Andrea M., and Tomlinson, Jeremy W.
- Subjects
Male ,Congenital Adrenal Hyperplasia ,salt-wasting CAH ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,plasma renin concentration ,ADDISONS-DISEASE ,030204 cardiovascular system & hematology ,Congenital Adrenal Hyperplasia, salt-wasting CAH, primary adrenal insufficiency, Mineralocorticoid replacement, plasma renin concentration, Fludrocortisone ,Biochemistry ,Plasma renin activity ,Primary Adrenal Insufficiency ,0302 clinical medicine ,Endocrinology ,Renin ,Medicine ,Longitudinal Studies ,Child ,Aged, 80 and over ,Univariate analysis ,Middle Aged ,ANGIOTENSIN-II ,Child, Preschool ,Fludrocortisone ,Female ,medicine.drug ,Adult ,medicine.medical_specialty ,Adolescent ,Hormone Replacement Therapy ,medicine.drug_class ,Urology ,030209 endocrinology & metabolism ,Context (language use) ,DIAGNOSIS ,Mineralocorticoid replacement ,03 medical and health sciences ,Young Adult ,Mineralocorticoids ,Internal medicine ,primary adrenal insufficiency ,MANAGEMENT ,Humans ,COHORT ,Congenital adrenal hyperplasia ,In patient ,HYPERPLASIA ,Aged ,Retrospective Studies ,Dose-Response Relationship, Drug ,business.industry ,Biochemistry (medical) ,Infant, Newborn ,Infant ,medicine.disease ,Blood pressure ,Mineralocorticoid ,business ,Adrenal Insufficiency - Abstract
Context No consensus exists for optimization of mineralocorticoid therapy in patients with primary adrenal insufficiency. Objective To explore the relationship between mineralocorticoid (MC) replacement dose, plasma renin concentration (PRC), and clinically important variables to determine which are most helpful in guiding MC dose titration in primary adrenal insufficiency. Design Observational, retrospective, longitudinal analysis. Patients A total of 280 patients (with 984 clinical visits and plasma renin measurements) with primary adrenal insufficiency were recruited from local databases and the international congenital adrenal hyperplasia (CAH) registry (www.i-cah.org). Thirty-seven patients were excluded from the final analysis due to incomplete assessment. Data from 204 patients with salt-wasting CAH (149 adults and 55 children) and 39 adult patients with Addison disease (AD) were analysed. Main outcome measures PRC, electrolytes, blood pressure (BP), and anthropometric parameters were used to predict their utility in optimizing MC replacement dose. Results PRC was low, normal, or high in 19%, 36%, and 44% of patients, respectively, with wide variability in MC dose and PRC. Univariate analysis demonstrated a direct positive relationship between MC dose and PRC in adults and children. There was no relationship between MC dose and BP in adults, while BP increased with increasing MC dose in children. Using multiple regression modeling, sodium was the only measurement that predicted PRC in adults. Longitudinally, the change in MC dose was able to predict potassium, but not BP or PRC. Conclusions The relationship between MC dose and PRC is complex and this may reflect variability in sampling with respect to posture, timing of last MC dose, adherence, and concomitant medications. Our data suggest that MC titration should not primarily be based only on PRC normalization, but also on clinical parameters such as BP and electrolyte concentration.
- Published
- 2020
24. Kidney Response to Heart Failure: Proteomic Analysis of Cardiorenal Syndrome
- Author
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Tereza Havlenova, Martin Chmel, Vojtech Melenovsky, Jiri Petrak, Ludek Cervenka, Janka Franeková, Matej Behounek, and Ondrej Viklicky
- Subjects
Male ,0301 basic medicine ,Proteomics ,lcsh:Diseases of the circulatory (Cardiovascular) system ,Proteome ,Receptor for Advanced Glycation End Products ,030204 cardiovascular system & hematology ,Kidney ,lcsh:RC870-923 ,Renin-Angiotensin System ,chemistry.chemical_compound ,0302 clinical medicine ,lcsh:Dermatology ,Extracellular Matrix Proteins ,General Medicine ,Up-Regulation ,medicine.anatomical_structure ,Nephrology ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,medicine.medical_specialty ,Cardiorenal syndrome ,Renal function ,Cardiomegaly ,Heart failure ,Peptidyl-Dipeptidase A ,03 medical and health sciences ,Kidney function ,Internal medicine ,medicine ,Albuminuria ,Animals ,Endothelium ,Creatinine ,Cardio-Renal Syndrome ,business.industry ,lcsh:RL1-803 ,medicine.disease ,lcsh:Diseases of the genitourinary system. Urology ,Angiotensin II ,Rats ,030104 developmental biology ,Endocrinology ,chemistry ,lcsh:RC666-701 ,Renal blood flow ,Angiotensin-II ,business - Abstract
Background/Aims: Chronic heart failure (HF) disrupts normal kidney function and leads to cardiorenal syndrome that further promotes HF progression. To identify potential participants in HF-related injury, we analyzed kidney proteome in an established HF model. Methods: HF was induced by chronic volume overload in male HanSD rats using aorto-caval fistula. After 21 weeks, cardiac and renal functions (in-situ kidney study) and renal proteomics were studied in sham-operated (controls) and HF rats, using iTRAQ labeling and LC-MS with Orbitrap Fusion, leading to identification and quantification of almost 4000 proteins. Results: Compared to controls, HF rats had cardiac hypertrophy, systemic and pulmonary congestion. Kidneys of HF rats had reduced renal blood flow, sodium excretion and urine production. While glomerular filtration rate, serum cystatin C and creatinine were still normal compared to controls, HF kidneys showed albuminuria and markedly increased tissue angiotensin-II levels (5-fold). HF kidneys (versus controls) displayed differential expression (˃1.5-fold) of 67 proteins. The most upregulated were angiotensin-converting enzyme (ACE, ˃20-fold), advanced glycosylation product-specific receptor (RAGE, 14-fold), periostin (6.8-fold), caveolin-1 (4.5-fold) and other proteins implicated in endothelial function (vWF, cavins 1-3, T-kininogen 2), proinflammatory ECM activation (MFAP4, collagen-VI, galectin-3, FHL-1, calponin) and proteins involved in glomerular filtration membrane integrity (CLIC5, ZO-1). Carboxylesterase-1D (CES1D), an enzyme that converts ACE inhibitors or sacubitril into active drugs, was also upregulated in HF kidneys. Conclusion: Chronic HF leads to latent kidney injury, associated with deep changes in kidney protein composition. These alterations may act in concert with intrarenal renin-angiotensin system activation and may serve as markers and/or targets to tackle cardiorenal syndrome.
- Published
- 2018
25. Cerebrospinal Fluid Changes in the Renin-Angiotensin System in Alzheimer's Disease
- Author
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Patrick G. Kehoe, James Scott Miners, Noura S K Al Mulhim, Kaj Blennow, and Henrik Zetterberg
- Subjects
0301 basic medicine ,Male ,Disease ,Renin-Angiotensin System ,0302 clinical medicine ,Cerebrospinal fluid ,angiotensin-(1-7) ,Barrier integrity ,angiotensin-II converting enyme-2 (ACE2) ,Aged, 80 and over ,General Neuroscience ,General Medicine ,Middle Aged ,Psychiatry and Mental health ,Clinical Psychology ,RENIN-ANGIOTENSIN SYSTEM ,medicine.anatomical_structure ,Blood-Brain Barrier ,Biomarker (medicine) ,Female ,Pericyte ,Angiotensin-Converting Enzyme 2 ,Alzheimer’s disease ,angiotensin-II converting enyme-1 (ACE1) ,medicine.medical_specialty ,Angiotensins ,tau Proteins ,Peptidyl-Dipeptidase A ,cerebrospinal fluid ,Receptor, Platelet-Derived Growth Factor beta ,03 medical and health sciences ,Alzheimer Disease ,Internal medicine ,Renin–angiotensin system ,medicine ,Humans ,angiotensin-II ,Aged ,Amyloid beta-Peptides ,business.industry ,Albumin ,Angiotensin II ,Peptide Fragments ,Capillaries ,030104 developmental biology ,Endocrinology ,Cross-Sectional Studies ,Geriatrics and Gerontology ,business ,030217 neurology & neurosurgery ,Biomarkers - Abstract
Observations in autopsied brain tissue indicate that overactivation of the classical renin-angiotensin system (cRAS) and underactivity within regulatory RAS pathways (rRAS) are associated with pathology in Alzheimer's disease (AD). The primary aim of this study was to investigate whether cerebrospinal fluid (CSF) markers of RAS are altered in AD in relation to established CSF markers of disease pathology (lower Aβ42 and elevated tau) and CSF markers of capillary dysfunction. We studied 40 controls and 40 AD cases grouped according to a biomarker profile (i.e., AD cases t-tau>400 pg/mL, pTau >60 pg/mL, and Aβ42
- Published
- 2019
26. Endothelial factors in the pathogenesis and treatment of chronic kidney disease Part I: General mechanisms: a joint consensus statement from the European Society of Hypertension Working Group on Endothelin and Endothelial Factors and The Japanese Society of Hypertension
- Author
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Peter W. de Leeuw, Patrick Rossignol, Naoyuki Hasebe, A.H. Jan Danser, Damiano Rizzoni, Neeraj Dhaun, Luis M. Ruilope, Gian Paolo Rossi, Matthias Barton, Sadayoshi Ito, Anton H. van den Meiracker, Teresa Maria Seccia, David J. Webb, Internal Medicine, Interne Geneeskunde, RS: CARIM - R3.02 - Hypertension and target organ damage, and MUMC+: MA Alg Interne Geneeskunde (9)
- Subjects
0301 basic medicine ,renal failure ,Physiology ,SMOOTH-MUSCLE-CELLS ,BLOOD-PRESSURE ,030204 cardiovascular system & hematology ,Bioinformatics ,Endothelins ,Renin-Angiotensin System ,0302 clinical medicine ,Medicine ,Endothelial dysfunction ,Aldosterone ,Kidney transplantation ,Endothelin-1 ,artery ,blood pressure ,PRIMARY ALDOSTERONISM ,SALT-SENSITIVE HYPERTENSION ,Vasodilation ,ANGIOTENSIN-II ,medicine.anatomical_structure ,diabetes mellitus ,CONVERTING ENZYME-ACTIVITY ,Cardiology and Cardiovascular Medicine ,endothelin ,Glomerular Filtration Rate ,medicine.hormone ,kidney ,Consensus ,hypertension ,Endothelium ,endothelium ,VASCULAR ENDOTHELIUM ,Vascular Remodeling ,Glycocalyx ,Preeclampsia ,A RECEPTOR ANTAGONISM ,03 medical and health sciences ,nitric oxide ,Internal Medicine ,Animals ,Humans ,Arterial Pressure ,Renal Insufficiency, Chronic ,NITRIC-OXIDE SYNTHASE ,atherosclerosis ,business.industry ,medicine.disease ,PROTEINURIC RENAL-DISEASE ,Angiotensin II ,Fibrosis ,Oxidative Stress ,030104 developmental biology ,Blood pressure ,Vasoconstriction ,Endothelium, Vascular ,business ,Kidney disease - Abstract
Kidney damage is a common consequence of arterial hypertension, but is also a cause of atherogenesis. Dysfunction and/or harm of the endothelium in glomeruli and tubular interstitium damage the function of these structures and translates into dynamic changes of filtration fraction, with progressive reduction in glomerular filtration rate, expansion of extracellular fluid volume, abnormal ion balance, and hypoxia, ultimately leading to chronic kidney disease. Considering the key role played by endothelial dysfunction in chronic kidney disease, the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension and the Japanese Society of Hypertension have critically reviewed available knowledge on the mechanisms underlying endothelial cell injury. This resulted into two articles: in the first, we herein examine the mechanisms by which endothelial factors induce vascular remodeling and the role of different players, including endothelin-1, the renin-angiotensin-aldosterone system and their interactions, and of oxidative stress; in the second, we discuss the role of endothelial dysfunction in the major disease conditions that affect the kidney.
- Published
- 2018
27. MicroRNA-221/222 Family Counteracts Myocardial Fibrosis in Pressure Overload-Induced Heart Failure
- Author
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Mitchell Bijnen, Tessa van Herwaarden, Michiel T H M Henkens, Wouter Verhesen, Marie-José Goumans, Marc van Bilsen, Frans A. van Nieuwenhoven, Arantxa González, Tim J Peters, Francisco J. Beaumont, Javier Díez, Rick van Leeuwen, Robin Verjans, Leon J. De Windt, Blanche Schroen, Stephane Heymans, Chantal Munts, Cardiologie, RS: CARIM - R2.02 - Cardiomyopathy, RS: CARIM - R2 - Cardiac function and failure, Promovendi CD, Interne Geneeskunde, RS: CARIM - R3.01 - Vascular complications of diabetes and the metabolic syndrome, RS: CARIM - R2.07 - Gene regulation, Fysiologie, RS: CARIM - R2.08 - Electro mechanics, and MUMC+: MA Med Staf Spec Cardiologie (9)
- Subjects
0301 basic medicine ,Male ,TISSUE GROWTH-FACTOR ,heart failure ,LIVER FIBROSIS ,Cardiovascular Medicine ,Proto-Oncogene Mas ,Mice ,Fibrosis ,Transforming Growth Factor beta ,remodeling ,exercise ,General Commentary ,cardiac hypertrophy ,Dilated cardiomyopathy ,CARDIAC FIBROBLASTS ,micoRNAs ,microRNAs ,ANGIOTENSIN-II ,Signal Transduction ,cardiomyopathies ,TRANSFORMING GROWTH-FACTOR-BETA-1 ,medicine.medical_specialty ,BILIARY ATRESIA ,Diastole ,HEPATIC STELLATE CELLS ,SMOOTH MUSCLE ACTIN ,03 medical and health sciences ,Internal medicine ,fibroblasts ,Internal Medicine ,medicine ,Animals ,Humans ,AORTIC-STENOSIS ,INHIBITS AUTOPHAGY ,Pressure overload ,business.industry ,Myocardium ,Aortic Valve Stenosis ,medicine.disease ,Angiotensin II ,Rats ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,Heart failure ,Hepatic stellate cell ,Myocardial fibrosis ,business - Abstract
Pressure overload causes cardiac fibroblast activation and transdifferentiation, leading to increased interstitial fibrosis formation and subsequently myocardial stiffness, diastolic and systolic dysfunction, and eventually heart failure. A better understanding of the molecular mechanisms underlying pressure overload-induced cardiac remodeling and fibrosis will have implications for heart failure treatment strategies. The microRNA (miRNA)-221/222 family, consisting of miR-221-3p and miR-222-3p, is differentially regulated in mouse and human cardiac pathology and inversely associated with kidney and liver fibrosis. We investigated the role of this miRNA family during pressure overload-induced cardiac remodeling. In myocardial biopsies of patients with severe fibrosis and dilated cardiomyopathy or aortic stenosis, we found significantly lower miRNA-221/222 levels as compared to matched patients with nonsevere fibrosis. In addition, miRNA-221/222 levels in aortic stenosis patients correlated negatively with the extent of myocardial fibrosis and with left ventricular stiffness. Inhibition of both miRNAs during AngII (angiotensin II)-mediated pressure overload in mice led to increased fibrosis and aggravated left ventricular dilation and dysfunction. In rat cardiac fibroblasts, inhibition of miRNA-221/222 derepressed TGF-beta (transforming growth factor-beta)-mediated profibrotic SMAD2 (mothers against decapentaplegic homolog 2) signaling and downstream gene expression, whereas overexpression of both miRNAs blunted TGF-beta-induced profibrotic signaling. We found that the miRNA-221/222 family may target several genes involved in TGF-beta signaling, including JNK1 (c-Jun N-terminal kinase 1), TGF-beta receptor 1 and TGF-beta receptor 2, and ETS-1 (ETS proto-oncogene 1). Our findings show that heart failure-associated downregulation of the miRNA-221/222 family enables profibrotic signaling in the pressure-overloaded heart.
- Published
- 2018
28. Biased ligand of the angiotensin II type 1 receptor in patients with acute heart failure
- Author
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Kathleen Goin, Gerasimos Filippatos, David G. Soergel, Sean P. Collins, Phillip D. Levy, David Bharucha, Gad Cotter, Beth A. Davison, Piotr Ponikowski, John R. Teerlink, Marco Metra, Peter S. Pang, Javed Butler, Adriaan A. Voors, G. Michael Felker, Justin A. Ezekowitz, and Cardiovascular Centre (CVC)
- Subjects
0301 basic medicine ,Male ,Biased ligand ,Acute heart failure ,Angiotensin-II ,Clinical trials ,Cardiology and Cardiovascular Medicine ,030204 cardiovascular system & hematology ,Cardiorespiratory Medicine and Haematology ,Cardiovascular ,GUIDELINES ,0302 clinical medicine ,Medicine ,Area under the curve ,Treatment Outcome ,Heart Disease ,6.1 Pharmaceuticals ,THERAPEUTICS ,Cardiology ,Female ,Patient Safety ,Drug ,Intravenous ,Oligopeptides ,medicine.medical_specialty ,Infusions ,Clinical Trials and Supportive Activities ,Clinical Sciences ,Placebo ,Dose-Response Relationship ,03 medical and health sciences ,Double-Blind Method ,Clinical Research ,Internal medicine ,MANAGEMENT ,Humans ,Aged ,Heart Failure ,Intention-to-treat analysis ,business.industry ,Surrogate endpoint ,MORTALITY ,Evaluation of treatments and therapeutic interventions ,Length of Stay ,Interim analysis ,medicine.disease ,EFFICACY ,Angiotensin II ,Surgery ,030104 developmental biology ,Blood pressure ,Cardiovascular System & Hematology ,Heart failure ,business ,Angiotensin II Type 1 Receptor Blockers ,TRV027 - Abstract
Aims: Currently, no acute heart failure (AHF) therapy definitively improves outcomes. Reducing morbidity and mortality from acute heart failure (AHF) remains an unmet need. TRV027 is a novel ` biased' ligand of the angiotensin II type 1 receptor (AT1R), selectively antagonizing the negative effects of angiotensin II, while preserving the potential pro-contractility effects of AT1R stimulation. BLAST-AHF was designed to determine the safety, efficacy, and optimal dose of TRV027 to advance into future studies.Methods and results: BLAST-AHF was a multi-centre, international, randomized, double-blind, placebo-controlled, parallel group, phase IIb dose-ranging study, enrolling patients with AHF into 4 groups: placebo, 1, 5, or 25mg/h of TRV027. Treatment was by IV infusion for 48-96 h. The primary composite endpoint was comprised of the following: (i) time from baseline to death through day 30, (ii) time from baseline to heart failure re-hospitalization through day 30, (iii) the first assessment time point following worsening heart failure through day 5, (iv) change in dyspnea visual analogue scale (VAS) score calculated as the area under the curve (AUC) representing the change from baseline over time from baseline through day 5, and (v) length of initial hospital stay (in days) from baseline. Analyses were by modified intention-to-treat. Overall, 621 patients were enrolled. After 254 patients, a pre-specified interim analysis resulted in several protocol changes, including a lower blood pressure inclusion criterion as well as a new allocation scheme of 2: 1: 2: 1, overweighting both placebo, and the 5mg/h dose. TRV027 did not confer any benefit over placebo at any dose with regards to the primary composite endpoint or any of the individual components. There were no significant safety issues with TRV027.Conclusion: In this phase IIb dose-ranging AHF study, TRV027 did not improve clinical status through 30-day follow-up compared with placebo.
- Published
- 2017
29. Angiotensin-III is Increased in Alzheimer’s Disease in Association with Amyloid-β and Tau Pathology
- Author
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Laura Palmer, Patrick G. Kehoe, Elliott Hibbs, and J Scott Miners
- Subjects
Male ,0301 basic medicine ,Angiotensin III ,renin-angiotensin system ,Cohort Studies ,Pathogenesis ,0302 clinical medicine ,Receptor ,aminopeptidase-P ,Aged, 80 and over ,biology ,General Neuroscience ,General Medicine ,Alzheimer's disease ,angiotensin-III ,Frontal Lobe ,Psychiatry and Mental health ,Clinical Psychology ,cardiovascular system ,Female ,hormones, hormone substitutes, and hormone antagonists ,medicine.medical_specialty ,Enzyme-Linked Immunosorbent Assay ,tau Proteins ,CD13 Antigens ,Glutamyl Aminopeptidase ,03 medical and health sciences ,Alzheimer Disease ,Internal medicine ,Renin–angiotensin system ,medicine ,Humans ,angiotensin-II ,Aged ,Analysis of Variance ,Amyloid beta-Peptides ,Angiotensin II receptor type 1 ,business.industry ,Angiotensin-converting enzyme ,medicine.disease ,aminopeptidase-A ,Angiotensin II ,030104 developmental biology ,Endocrinology ,biology.protein ,Geriatrics and Gerontology ,business ,030217 neurology & neurosurgery - Abstract
Hyperactivity of the renin-angiotensin system (RAS) is associated with the pathogenesis of Alzheimer’s disease (AD) believed to be mediated by angiotensin-II (Ang-II) activation of the angiotensin type 1 receptor (AT1R). We previously showed that angiotensin-converting enzyme-1 (ACE-1) activity, the rate-limiting enzyme in the production of Ang-II, is increased in human postmortem brain tissue in AD. Angiotensin-III (Ang-III) activates the AT1R and angiotensin type-2 receptor (AT2R), but its potential role in the pathophysiology of AD remains unexplored. We measured Ang-II and Ang-III levels by ELISA, and the levels and activities of aminopeptidase-A (AP-A) and aminopeptidase-N (AP-N) (responsible for the production and metabolism of Ang-III, respectively) in human postmortem brain tissue in the mid-frontal cortex (Brodmann area 9) in a cohort of AD (n = 90) and age-matched non-demented controls (n = 59), for which we had previous measurements of ACE-1 activity, Aβ level, and tau pathology (also in the mid-frontal cortex). We found that both Ang-II and Ang-III levels were significantly higher in AD compared to age-matched controls and that Ang-III, rather than Ang-II, was strongly associated with Aβ load and tau load. Levels of AP-A were significantly reduced in AD but AP-A enzyme activity was unchanged whereas AP-N activity was reduced in AD but AP-N protein level was unchanged. Together, these data indicate that the APA/Ang-III/APN/Ang-IV/AT4R pathway is dysregulated and that elevated Ang-III could contribute to the pathogenesis of AD.
- Published
- 2017
30. Rapid Aldosterone-Mediated Signaling in the DCT Increases Activity of the Thiazide-Sensitive NaCl Cotransporter
- Author
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Qi Wu, Robert A. Fenton, Emma T. B. Olesen, Trairak Pisitkun, Timo Rieg, Henrik Dimke, Li Peng, Cristina Esteva-Font, L. M. Fredrik Leeb-Lundberg, Lei Cheng, Søren Brandt Poulsen, and Björn Olde
- Subjects
Male ,Proteomics ,030232 urology & nephrology ,Blood Pressure ,BLOOD-PRESSURE ,Sodium Chloride ,Kidney ,Receptors, G-Protein-Coupled ,Thiazides ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,cotransporter ,Cyclic AMP ,mineralocorticoid ,Solute Carrier Family 12, Member 3 ,Phosphorylation ,Kidney Tubules, Distal ,PHOSPHORYLATION ,Aldosterone ,0303 health sciences ,NCC ,Chemistry ,Kinase ,SPAK ,systems biology ,General Medicine ,Na transport ,3. Good health ,Cell biology ,ErbB Receptors ,PROTEIN-COUPLED RECEPTOR ,ANGIOTENSIN-II ,ESTROGEN ,medicine.anatomical_structure ,Receptors, Estrogen ,Nephrology ,Gitelman Syndrome ,Signal Transduction ,medicine.drug_class ,Cell Line ,03 medical and health sciences ,In vivo ,Mineralocorticoids ,medicine ,Animals ,Distal convoluted tubule ,CL-COTRANSPORTER ,Protein kinase B ,030304 developmental biology ,urogenital system ,Cell Membrane ,Computational Biology ,REFERENCE VALUES ,SODIUM-CHLORIDE COTRANSPORTER ,Basic Research ,Mineralocorticoid ,MINERALOCORTICOID-RECEPTOR ,Calcium ,epidermal growth factor receptor ,Ex vivo - Abstract
BACKGROUND: The NaCl cotransporter NCC in the kidney distal convoluted tubule (DCT) regulates urinary NaCl excretion and BP. Aldosterone increases NaCl reabsorption via NCC over the long-term by altering gene expression. But the acute effects of aldosterone in the DCT are less well understood.METHODS: Proteomics, bioinformatics, and cell biology approaches were combined with animal models and gene-targeted mice.RESULTS: Aldosterone significantly increases NCC activity within minutes in vivo or ex vivo. These effects were independent of transcription and translation, but were absent in the presence of high potassium. In vitro, aldosterone rapidly increased intracellular cAMP and inositol phosphate accumulation, and altered phosphorylation of various kinases/kinase substrates within the MAPK/ERK, PI3K/AKT, and cAMP/PKA pathways. Inhibiting GPR30, a membrane-associated receptor, limited aldosterone's effects on NCC activity ex vivo, and NCC phosphorylation was reduced in GPR30 knockout mice. Phosphoproteomics, network analysis, and in vitro studies determined that aldosterone activates EGFR-dependent signaling. The EGFR immunolocalized to the DCT and EGFR tyrosine kinase inhibition decreased NCC activity ex vivo and in vivo.CONCLUSIONS: Aldosterone acutely activates NCC to modulate renal NaCl excretion.
- Published
- 2019
31. Human umbilical cord mesenchymal stem cells pretreated with Angiotensin-II attenuate pancreas injury of rats with severe acute pancreatitis
- Author
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Ying Zhu, Bing-Wei Liu, Ming-Li Zhu, Xiao-Kang Zeng, Wei-Ying Dai, Shaosong Xi, Jing Yang, Xian-Fu Ke, Wei Hu, Jun Su, and Huapeng Lin
- Subjects
0301 basic medicine ,Angiogenesis ,Endothelial cells ,Neovascularization, Physiologic ,Apoptosis ,RM1-950 ,Pharmacology ,Mesenchymal Stem Cell Transplantation ,Umbilical cord ,Models, Biological ,Umbilical vein ,Umbilical Cord ,03 medical and health sciences ,0302 clinical medicine ,Paracrine Communication ,Human Umbilical Vein Endothelial Cells ,Medicine ,Animals ,Humans ,Pancreas ,Tube formation ,business.industry ,Angiotensin II ,Mesenchymal stem cell ,hUC-MSCs ,Mesenchymal Stem Cells ,General Medicine ,medicine.disease ,Vascular Endothelial Growth Factor Receptor-2 ,Rats ,Endothelial stem cell ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Pancreatitis ,030220 oncology & carcinogenesis ,Culture Media, Conditioned ,Acute Disease ,cardiovascular system ,Angiotensin-II ,Therapeutics. Pharmacology ,business ,SAP - Abstract
Mesenchymal stem cells (MSCs) pretreatment is an effective route for improving cell-based therapy of endothelial cell survival, vascular stabilization, and angiogenesis. We hypothesized that the application of human umbilical cord-MSCs (hUC-MSCs) pretreated with angiotensin-II (Ang-II) might be a potential therapeutic approach for severe acute pancreatitis (SAP). Therefore, the effect of Ang-II pretreated hUC-MSCs on SAP was investigated in vitro and in vivo. Methods In the present study, human umbilical cord-derived MSCs pretreated with or without Ang-II were delivered through the tail vein of rats 12 h after induction of SAP. Pancreatitis severity scores and serum lipase levels, as well as the levels of VEGF and VEGFR2 were evaluated. Results We found that the administration of Ang-II-MSCs significantly inhibited pancreatic injury, as reflected by reductions of pancreatitis severity scores, serum amylase and serum lipase levels. Furthermore, the reduced apoptotic rate and increased tube formation in human umbilical vein endothelial Cells (HUVEC) were found resulting from the administration of Ang-II-MSC-CM. Moreover, knockdown of VEGFR2 can block the effect of Ang-II-MSC-CM on preventing HUVEC from apoptosis, as well as the capacity of tube formation was also suppressed. In addition, the expression of increased Bcl-2 and alleviated caspase-3 were observed in HUVEC and HUVEC transfectants exposure to Ang-II-MSC-CM. Conclusion Collectively, these results elucidated that the pretreatment of hUC-MSCs with Ang-II improved the outcome of MSC-based therapy for SAP via enhancing angiogenesis and ameliorating endothelial cell dysfunction in a VEGFR2 dependent manner.
- Published
- 2019
32. The association of calcium channel blockers with β-cell function in type 2 diabetic patients: A cross-sectional study
- Author
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Yuanyuan Zhang, Yu Cao, Dong Zhao, Ying-Mei Feng, Ning Zhang, Cai-Guo Yu, Jan A. Staessen, Sha-Sha Yuan, Epidemiologie, RS: CARIM - R3.02 - Hypertension and target organ damage, and RS: Carim - V02 Hypertension and target organ damage
- Subjects
Blood Glucose ,Male ,endocrine system diseases ,Cross-sectional study ,calcium channel blocker ,type 2 diabetes mellitus ,Endocrinology, Diabetes and Metabolism ,Calcium channel blocker ,030204 cardiovascular system & hematology ,Gastroenterology ,0302 clinical medicine ,HYPERTENSIVE PATIENTS ,Insulin-Secreting Cells ,Medicine ,030212 general & internal medicine ,PROTECTION ,C-Peptide ,Fasting ,ER STRESS ,Middle Aged ,Calcium Channel Blockers ,PREVALENCE ,ANGIOTENSIN-II ,Hypertension ,ALDOSTERONE ,Female ,Cardiology and Cardiovascular Medicine ,Glucose intake ,Adult ,β cell function ,medicine.medical_specialty ,inhibitor of renin-angiotensin-aldosterone system ,medicine.drug_class ,INHIBITION ,Therapeutics ,03 medical and health sciences ,Negatively associated ,Internal medicine ,Internal Medicine ,Humans ,Antihypertensive Agents ,Aged ,Glycated Hemoglobin ,business.industry ,beta-cell function ,Calcium channel ,RENIN ,Type 2 Diabetes Mellitus ,nutritional and metabolic diseases ,Cross-Sectional Studies ,Diabetes Mellitus, Type 2 ,RECEPTOR BLOCKADE ,business ,Homeostasis ,SYSTEM - Abstract
Type 2 diabetes mellitus (T2DM) patients are often accompanied with hypertension. However, the association of antihypertensive drugs with β-cell function has not been well studied. To investigate this question, the authors performed a cross-sectional study involving 882 hypertensive T2DM patients. To assess β-cell function, patients were given 75g glucose orally and C-peptide levels before and 1, 2, and 3 hours after glucose intake were measured. Homa-β was computed by Homeostasis Model Assessment model to evaluate β-cell function using fasting C-peptide and glucose levels in the plasma. Multivariable-adjusted analysis was performed to evaluate the association of antihypertensive drugs with C-peptide levels, HbA1c, and Homa-β. Among 882 hypertensive patients, 547 (62.0%) received antihypertensive treatment. Multivariate-adjusted analysis demonstrated that use of calcium channel blockers (CCBs) was negatively associated with HbA1c levels (CCBs: 0.95 [95% CI: 0.92-0.98], P = 0.002). Our data further illustrated that the C-peptide levels before and 1, 2, and 3 hours of OGTT were 1.10-, 1.18-, 1.19-, and 1.15-fold increase in T2DM patients taking CCBs (P = 0.084 for fasting C-peptide levels; P ≤ 0.024 for C-peptide levels at 1, 2, and 3 hours after OGTT) in comparison with non-CCB users. Nevertheless, usage of any other antihypertensive drugs did neither associated with HbA1c nor associated with C-peptide levels (P ≥ 0.11). In conclusion, CCB treatment was negatively associated with HbA1c levels but positively associated with β-cell function in hypertensive T2DM patients, implying that CCBs could be considered to treat hypertensive T2DM patients with reduced β-cell function.
- Published
- 2018
33. The epidermal growth factor receptor pathway in chronic kidney diseases
- Author
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Ron T. Gansevoort, Esther Meijer, Laura R. Harskamp, and Harry van Goor
- Subjects
0301 basic medicine ,Autosomal dominant polycystic kidney disease ,Kidney ,DIABETIC-NEPHROPATHY ,Diabetic nephropathy ,03 medical and health sciences ,Chronic allograft nephropathy ,medicine ,Renal fibrosis ,Polycystic kidney disease ,Animals ,Humans ,RENAL FIBROSIS ,Epidermal growth factor receptor ,Renal Insufficiency, Chronic ,INSULIN-RESISTANCE ,biology ,business.industry ,IN-SITU HYBRIDIZATION ,medicine.disease ,ALPHA-CONVERTING-ENZYME ,ErbB Receptors ,NORMAL HUMAN ADULT ,Disease Models, Animal ,ANGIOTENSIN-II ,030104 developmental biology ,medicine.anatomical_structure ,Nephrology ,Immunology ,Cancer research ,biology.protein ,business ,TYROSINE KINASE-ACTIVITY ,MESSENGER-RNA ,EGF-RECEPTOR ,Kidney disease ,Signal Transduction - Abstract
The epidermal growth factor receptor (EGFR) pathway has a critical role in renal development, tissue repair and electrolyte handling. Numerous studies have reported an association between dysregulation of this pathway and the initiation and progression of various chronic kidney diseases such as diabetic nephropathy, chronic allograft nephropathy and polycystic kidney disease through the promotion of renal cell proliferation, fibrosis and inflammation. In the oncological setting, compounds that target the EGFR pathway are already in clinical use or have been evaluated in clinical trials; in the renal setting, therapeutic interventions targeting this pathway by decreasing ligand availability with disintegrin and metalloproteinase inhibitors or with ligand-neutralizing antibodies, or by inhibiting receptor activation with tyrosine kinase inhibitors or monoclonal antibodies are only just starting to be explored in animal models of chronic kidney disease and in patients with autosomal dominant polycystic kidney disease. In this Review we focus on the role of the EGFR signalling pathway in the kidney under physiological conditions and during the pathophysiology of chronic kidney diseases and explore the clinical potential of interventions in this pathway to treat chronic renal diseases.
- Published
- 2016
34. In Primary Aldosteronism, Mineralocorticoids Influence Exosomal Sodium-Chloride Cotransporter Abundance
- Author
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Aihua Wu, Shengxin Xu, Robert A. Fenton, Martin Wolley, Richard D. Gordon, and Michael Stowasser
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,URINARY EXOSOMES ,medicine.drug_class ,Fludrocortisone ,DISTAL CONVOLUTED TUBULE ,NA-CL COTRANSPORTER ,PROTEIN ,BLOOD-PRESSURE ,030204 cardiovascular system & hematology ,Exosomes ,RESISTANT HYPERTENSION ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Primary aldosteronism ,Mineralocorticoids ,Internal medicine ,Hyperaldosteronism ,medicine ,Humans ,PHOSPHORYLATION ,Protein kinase A ,WNK4-SPAK-DEPENDENT PATHWAY ,Aldosterone ,urogenital system ,Chemistry ,KINASES ,General Medicine ,Middle Aged ,medicine.disease ,Sodium Chloride Symporters ,WNK4 ,ANGIOTENSIN-II ,030104 developmental biology ,Endocrinology ,Nephrology ,Mineralocorticoid ,Female ,Brief Communications ,Cotransporter ,medicine.drug - Abstract
Distal tubular sodium retention is a potent driver of hypertension, and the thiazide–sensitive sodium-chloride cotransporter (NCC) has a key role in this process. In humans, factors regulating NCC are unclear, but in animal models, aldosterone is a potent regulator, possibly via effects on plasma potassium. We studied the effects of the mineralocorticoid fludrocortisone on the abundance of NCC and its phosphorylated form (pNCC) as well as WNK lysine deficient protein kinase 4 (WNK4) and STE20/SPS1–related, proline alanine–rich kinase (SPAK) in human urinary exosomes. We isolated exosomes from daily urine samples in 25 patients undergoing fludrocortisone suppression testing (100 μg every 6 hours for 4 days) to diagnose or exclude primary aldosteronism. Over the course of the test, NCC levels increased 3.68-fold (P
- Published
- 2016
35. Postmortem blood concentrations of sartans measured by liquid chromatography-tandem mass spectrometry
- Author
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Merja Gergov, Raimo A. Ketola, Medicum, and Forensic Medicine
- Subjects
PHARMACOKINETICS ,Internal standard ,HUMAN URINE ,Angiotensin II receptor antagonists ,II RECEPTOR ANTAGONISTS ,Blood concentration ,Toxicology ,030226 pharmacology & pharmacy ,01 natural sciences ,High-performance liquid chromatography ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Liquid chromatography–mass spectrometry ,medicine ,DRUGS ,HUMAN PLASMA ,Solid phase extraction ,LC-MS/MS ,Active metabolite ,Chromatography ,Chemistry ,010401 analytical chemistry ,Biochemistry (medical) ,Selected reaction monitoring ,319 Forensic science and other medical sciences ,Angiotensin II ,0104 chemical sciences ,TELMISARTAN ,SOLID-PHASE EXTRACTION ,ANGIOTENSIN-II ,Postmortem ,Losartan ,Sartans ,LOSARTAN ,HPLC ,medicine.drug - Abstract
A liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the analysis of seven common sartans (candesartan, eprosartan, losartan, olmesartan, telmisartan, valsartan, and losartan carboxylic acid (EXP3174), the active metabolite of losartan) in postmortem blood samples with liquid-liquid extraction. Detection was accomplished by triple-quadrupole MS in the selected reaction monitoring mode. The validation procedure showed low limits of quantitation of 5 ng/mL for all compounds with good accuracy and precision. The matrix effect was evaluated from the variation of peak areas and concentrations. The method shows some matrix effect but the effect was efficiently compensated by using an internal standard method. The method was applied to the analysis of sartans in postmortem blood samples, and produced 534 positive findings during 2014-2015. Nine deaths were encountered where the concentration of a sartan was very high, indicating intoxication together with other causes of death or multi-drug intoxication. The quantitative results indicate that sartans do not show significant postmortem redistribution; thus concentrations higher than the therapeutic range can be considered as being toxic or fatal.
- Published
- 2016
36. Dynamic Interstitial Cell Response during Myocardial Infarction Predicts Resilience to Rupture in Genetically Diverse Mice
- Author
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Mandy Chen, Kaesi A. Morelli, Olivia J Hon, Milena B. Furtado, Sandra Daigle, Elvira Forte, Vivek M. Philip, Daniel A. Skelly, Mauro W. Costa, and Nadia Rosenthal
- Subjects
0301 basic medicine ,Pathology ,Cell ,0601 Biochemistry and Cell Biology ,Mice ,0302 clinical medicine ,Fibrosis ,Homeostasis ,HETEROGENEITY ,RNA-SEQ ,Myocardial infarction ,050207 economics ,Myofibroblasts ,lcsh:QH301-705.5 ,050208 finance ,05 social sciences ,genetic diversity ,scRNAseq ,cardiac rupture ,ANGIOTENSIN-II ,Phenotype ,myocardial infarction ,medicine.anatomical_structure ,Single-Cell Analysis ,CONTRIBUTE ,Pericardium ,Life Sciences & Biomedicine ,Myofibroblast ,EXPRESSION ,CARDIAC PROGENITOR CELLS ,FIBROBLASTS ,medicine.medical_specialty ,Stromal cell ,MIGRATION ,Mice, Inbred Strains ,heart ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Interstitial cell ,Cicatrix ,03 medical and health sciences ,0502 economics and business ,medicine ,Animals ,epicardial-derived ,mouse ,Rupture ,Science & Technology ,Myocardium ,VIII COLLAGEN ,fibrosis ,Cardiac Rupture ,single-cell biology ,Cell Biology ,medicine.disease ,030104 developmental biology ,MRNA Sequencing ,lcsh:Biology (General) ,Seurat ,1116 Medical Physiology ,Stromal Cells ,030217 neurology & neurosurgery - Abstract
Summary Cardiac ischemia leads to the loss of myocardial tissue and the activation of a repair process that culminates in the formation of a scar whose structural characteristics dictate propensity to favorable healing or detrimental cardiac wall rupture. To elucidate the cellular processes underlying scar formation, here we perform unbiased single-cell mRNA sequencing of interstitial cells isolated from infarcted mouse hearts carrying a genetic tracer that labels epicardial-derived cells. Sixteen interstitial cell clusters are revealed, five of which were of epicardial origin. Focusing on stromal cells, we define 11 sub-clusters, including diverse cell states of epicardial- and endocardial-derived fibroblasts. Comparing transcript profiles from post-infarction hearts in C57BL/6J and 129S1/SvImJ inbred mice, which displays a marked divergence in the frequency of cardiac rupture, uncovers an early increase in activated myofibroblasts, enhanced collagen deposition, and persistent acute phase response in 129S1/SvImJ mouse hearts, defining a crucial time window of pathological remodeling that predicts disease outcome., Graphical Abstract, Highlights • Longitudinal transcriptional profiling of cardiac interstitial cells post-infarct • Identification of epicardial versus endocardial origin of cardiac stromal cells • A distinct early injury-response signature precedes appearance of myofibroblasts • Modulation of early fibrosis predicts cardiac rupture and pathological remodeling, Using single-cell transcriptional profiling of mouse hearts carrying a reporter for epicardial-derived cells, Forte et al. provide a dynamic view of cardiac interstitial responses across acute and chronic phases of remodeling post-infarction. Comparing responses on diverse genetic backgrounds reveals novel cellular and transcriptional features of cardiac rupture propensity.
- Published
- 2020
37. Targeted HFpEF therapy based on matchmaking of human and animal models
- Author
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Vanessa P. M. van Empel, Marc van Bilsen, Arantxa Barandiarán Aizpurua, and Blanche Schroen
- Subjects
0301 basic medicine ,heart failure with preserved ejection fraction ,Physiology ,Cardiac fibrosis ,Inflammation ,030204 cardiovascular system & hematology ,Bioinformatics ,Translational Research, Biomedical ,03 medical and health sciences ,CHRONIC INHIBITION ,0302 clinical medicine ,LEFT-VENTRICULAR FUNCTION ,Physiology (medical) ,Medicine ,Animals ,Humans ,Endothelial dysfunction ,CARDIAC FIBROSIS ,MYOCARDIAL DYSFUNCTION ,Heart Failure ,biology ,business.industry ,C-reactive protein ,Stroke Volume ,personalized medicine ,DIASTOLIC DYSFUNCTION ,medicine.disease ,Angiotensin II ,Pathophysiology ,CHRONIC HEART-FAILURE ,C-REACTIVE PROTEIN ,ANGIOTENSIN-II ,Disease Models, Animal ,030104 developmental biology ,translational research ,PRESERVED EJECTION FRACTION ,inflammation ,ENDOTHELIAL DYSFUNCTION ,biology.protein ,trial design ,Personalized medicine ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Heart failure with preserved ejection fraction ,business - Abstract
Targeted HFpEF therapy based on matchmaking of human and animal models. Am J Physiol Heart Circ Physiol 315: H1670-H1683, 2018. First published September 21, 2018; doi:10.1152/ajpheart.00024.2018. The diversity in clinical phenotypes and poor understanding of the underlying pathophysiology of heart failure with preserved ejection fraction (HFpEF) is the main reason why no effective treatments have been found yet. Targeted, instead of one size fits all, treatment seems the only promising approach for treating 1114pE14. To be able to design a targeted, phenotype-specific HFpEF treatment, the matrix relating clinical phenotypes and underlying pathophysiological mechanisms has to be clarified. This review discusses the opportunities for additional evaluation of the underlying pathophysiological processes, e.g., to evaluate biological phenotypes on top of clinical routine, to guide us toward a phenotype specific HFpEF treatment. Moreover, a translational approach with matchmaking of animal models to biological HFpEF phenotypes will be a valuable step to test the effectiveness of novel, targeted interventions in IIFpEF.
- Published
- 2018
38. The Role of Oxidative Stress in the Development of Systemic Sclerosis Related Vasculopathy
- Author
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Douwe J. Mulder, Gilles F. H. Diercks, Martin Feelisch, Amaal Eman Abdulle, and Harry van Goor
- Subjects
0301 basic medicine ,systemic sclerosis ,Physiology ,Inflammation ,Review ,HEAT-SHOCK-PROTEIN ,medicine.disease_cause ,lcsh:Physiology ,Autoimmunity ,Pathogenesis ,03 medical and health sciences ,HYDROGEN-PEROXIDE ,0302 clinical medicine ,Fibrosis ,Physiology (medical) ,NADPH OXIDASE ,medicine ,NITRIC-OXIDE SYNTHASE ,Endothelial dysfunction ,vasculopathy ,development ,intervention ,reactive oxygen species ,030203 arthritis & rheumatology ,RAYNAUDS-PHENOMENON SECONDARY ,lcsh:QP1-981 ,integumentary system ,business.industry ,ANTIENDOTHELIAL CELL ANTIBODIES ,medicine.disease ,Connective tissue disease ,Angiotensin II ,OXYGEN SPECIES GENERATION ,ANGIOTENSIN-II ,030104 developmental biology ,ENDOTHELIAL GROWTH-FACTOR ,Immunology ,biomarker ,REACTIVE OXYGEN ,medicine.symptom ,business ,Oxidative stress - Abstract
Systemic sclerosis (SSc) is a rare connective tissue disease characterized by autoimmunity, vasculopathy, and progressive fibrosis typically affecting multiple organs including the skin. SSc often is a lethal disorder, because effective disease-modifying treatment still remains unavailable. Vasculopathy with endothelial dysfunction, perivascular infiltration of mononuclear cells, vascular wall remodeling and rarefaction of capillaries is the hallmark of the disease. Most patients present with vasospastic attacks of the digital arteries referred to as ‘Raynaud’s phenomenon,’ which is often an indication of an underlying widespread vasculopathy. Although autoimmune responses and inflammation are both found to play an important role in the pathogenesis of this vasculopathy, no definite initiating factors have been identified. Recently, several studies have underlined the potential role of oxidative stress in the pathogenesis of SSc vasculopathy thereby proposing a new aspect in the pathogenesis of this disease. For instance, circulating levels of reactive oxygen species (ROS) related markers have been found to correlate with SSc vasculopathy, the formation of fibrosis and the production of autoantibodies. Excess ROS formation is well-known to lead to endothelial cell (EC) injury and vascular complications. Collectively, these findings suggest a potential role of ROS in the initiation and progression of SSc vasculopathy. In this review, we present the background of oxidative stress related processes (e.g., EC injury, autoimmunity, inflammation, and vascular wall remodeling) that may contribute to SSc vasculopathy. Finally, we describe the use of oxidative stress related read-outs as clinical biomarkers of disease activity and evaluate potential anti-oxidative strategies in SSc.
- Published
- 2018
39. Nitric Oxide Synthase Inhibition Induces Renal Medullary Hypoxia in Conscious Rats
- Author
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Tonja W. Emans, Jaap A. Joles, C. T. Paul Krediet, Ben J. A. Janssen, General Internal Medicine, Farmacologie en Toxicologie, and RS: CARIM - R2.03 - ECM + Wnt signaling
- Subjects
Male ,Nephrology and Kidney ,HYPERTENSIVE RAT ,BLOCKADE ,030232 urology & nephrology ,Blood Pressure ,030204 cardiovascular system & hematology ,Nitroarginine ,chemistry.chemical_compound ,0302 clinical medicine ,Renal hypoxia ,TISSUE OXYGENATION ,Medicine ,No production ,Enzyme Inhibitors ,Original Research ,Kidney Medulla ,L-ARGININE ,biology ,nitric oxide synthase ,telemetry ,oxygen consumption ,Nitric oxide synthase ,Proteinuria ,ANGIOTENSIN-II ,Hypertension ,NO PRODUCTION ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Glomerular Filtration Rate ,medicine.medical_specialty ,Kidney Cortex ,Medullary cavity ,KIDNEY OXYGENATION ,PRESSURE ,Nitric oxide ,Renal Circulation ,03 medical and health sciences ,Internal medicine ,Animals ,renal oxygenation ,BLOOD-FLOW ,business.industry ,hypoxia ,Sodium ,Hemodynamics ,Hypoxia (medical) ,medicine.disease ,Angiotensin II ,Rats ,Oxygen ,Endocrinology ,chemistry ,biology.protein ,business ,Kidney disease ,RESPONSES - Abstract
Background Renal hypoxia, implicated as crucial factor in onset and progression of chronic kidney disease, may be attributed to reduced nitric oxide because nitric oxide dilates vasculature and inhibits mitochondrial oxygen consumption. We hypothesized that chronic nitric oxide synthase inhibition would induce renal hypoxia. Methods and Results Oxygen‐sensitive electrodes, attached to telemeters, were implanted in either renal cortex (n=6) or medulla (n=7) in rats. After recovery and stabilization, baseline oxygenation ( pO 2 ) was recorded for 1 week. To inhibit nitric oxide synthase, N‐ω‐nitro‐ l ‐arginine (L‐NNA; 40 mg/kg/day) was administered via drinking water for 2 weeks. A separate group (n=8), instrumented with blood pressure telemeters, followed the same protocol. L‐NNA rapidly induced hypertension (165±6 versus 108±3 mm Hg; P P pO 2 , after initially dipping, returned to baseline and then increased. Medullary pO 2 decreased progressively (up to −19±6% versus baseline; P pO 2 was decreased (3.7 [2.2–5.3] versus 7.9 [7.5–8.4]; P pO 2 were unaltered. Terminal glomerular filtration rate (1374±74 versus 2098±122 μL/min), renal blood flow (5014±336 versus 9966±905 μL/min), and sodium reabsorption efficiency (13.0±0.8 versus 22.8±1.7 μmol/μmol) decreased (all P Conclusions For the first time, we show temporal development of renal cortical and medullary oxygenation during chronic nitric oxide synthase inhibition in unrestrained conscious rats. Whereas cortical pO 2 shows transient changes, medullary pO 2 decreased progressively. Chronic L‐NNA leads to decreased renal perfusion and sodium reabsorption efficiency, resulting in progressive medullary hypoxia, suggesting that juxtamedullary nephrons are potentially vulnerable to prolonged nitric oxide depletion.
- Published
- 2018
40. A Typical Immune T/B Subset Profile Characterizes Bicuspid Aortic Valve: In an Old Status?
- Author
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Calogera Pisano, Carmela Rita Balistreri, Giovanni Ruvolo, Giacomo Frati, Antonino G.M. Marullo, Domenico Lio, Giuseppina Colonna-Romano, Sebastiano Sciarretta, Sonia Schiavon, Alberto Allegra, Giuseppe Mazzesi, Ernesto Greco, Elena Cavarretta, Silvio Buffa, Silvia Palmerio, Balistreri, Carmela R, Buffa, Silvio, Allegra, Alberto, Pisano, Calogera, Ruvolo, Giovanni, Colonna-Romano, Giuseppina, Lio, Domenico, Mazzesi, Giuseppe, Schiavon, Sonia, Greco, Ernesto, Palmerio, Silvia, Sciarretta, Sebastiano, Cavarretta, Elena, Marullo, Antonino G M, and Frati, Giacomo
- Subjects
Male ,0301 basic medicine ,Aortic valve ,Aging ,T-Lymphocytes ,Lymphocyte ,Heart Valve Diseases ,030204 cardiovascular system & hematology ,Biochemistry ,Immunoglobulin D ,0302 clinical medicine ,Bicuspid aortic valve ,Bicuspid Aortic Valve Disease ,Bicuspid aortic valve, aneurysm, B cells ,b-cells ,notch1 ,Invariant t-cells ,aneurysm formation ,angiotensin-ii ,signaling pathway ,genetic-variants ,apoptotic cells ,mechanisms ,mutations ,B-Lymphocytes ,biology ,lcsh:Cytology ,hemic and immune systems ,General Medicine ,Middle Aged ,medicine.anatomical_structure ,Aortic Valve ,Cardiology ,cardiovascular system ,Female ,Research Article ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Article Subject ,T cell ,Naive B cell ,chemical and pharmacologic phenomena ,Thoracic aortic aneurysm ,03 medical and health sciences ,Bicuspid valve ,Internal medicine ,medicine ,Humans ,Settore MED/05 - Patologia Clinica ,cardiovascular diseases ,lcsh:QH573-671 ,B cells ,business.industry ,Settore MED/23 - Chirurgia Cardiaca ,Cell Biology ,medicine.disease ,030104 developmental biology ,biology.protein ,aneurysm ,business ,A Typical Immune T/B Subset Profile, Bicuspid Aortic Valve - Abstract
Bicuspid valve disease is associated with the development of thoracic aortic aneurysm. The molecular mechanisms underlying this association still need to be clarified. Here, we evaluated the circulating levels of T and B lymphocyte subsets associated with the development of vascular diseases in patients with bicuspid aortic valve or tricuspid aortic valve with and without thoracic aortic aneurysm. We unveiled that the circulating levels of the MAIT, CD4+IL−17A+, and NKT T cell subsets were significantly reduced in bicuspid valve disease cases, when compared to tricuspid aortic valve cases in either the presence or the absence of thoracic aortic aneurysm. Among patients with tricuspid aortic valve, these cells were higher in those also affected by thoracic aortic aneurysm. Similar data were obtained by examining CD19+ B cells, naïve B cells (IgD+CD27−), memory unswitched B cells (IgD+CD27+), memory switched B cells (IgD−CD27+), and double-negative B cells (DN) (IgD−CD27−). These cells resulted to be lower in subjects with bicuspid valve disease with respect to patients with tricuspid aortic valve. In whole, our data indicate that patients with bicuspid valve disease show a quantitative reduction of T and B lymphocyte cell subsets. Future studies are encouraged to understand the molecular mechanisms underlying this observation and its pathophysiological significance.
- Published
- 2018
41. Perioperative management of angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers: a survey of perioperative medicine practitioners
- Author
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Rupert M Pearse, Tom E.F. Abbott, Gareth L. Ackland, S.L.M. Walker, and Katherine Brown
- Subjects
medicine.medical_specialty ,Surgery and Surgical Specialties ,lcsh:Medicine ,General Biochemistry, Genetics and Molecular Biology ,Anaesthesia ,03 medical and health sciences ,0302 clinical medicine ,030202 anesthesiology ,Anesthesiology ,Medicine ,030212 general & internal medicine ,cardiovascular diseases ,Survey ,Anesthesiology and Pain Management ,Perioperative medicine ,Perioperative management ,biology ,business.industry ,General Neuroscience ,lcsh:R ,Noncardiac surgery ,Angiotensin-converting enzyme ,General Medicine ,Angiotensin II ,Ethical Issues ,Anesthesia ,Myocardial injury ,biology.protein ,Angiotensin-II ,Angiotensin Receptor Blockers ,Hypotension ,General Agricultural and Biological Sciences ,business - Abstract
BackgroundAngiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are the most commonly prescribed antihypertensive medications in higher-risk surgical patients. However, there is no clinical consensus on their use in the perioperative period, in part, due to an inconsistent evidence-base. To help inform the design of a large multi-centre randomized controlled trial (ISRCTN17251494), we undertook a questionnaire-based survey exploring variability in ACEi/ARB prescribing in perioperative practice.MethodsThe online survey included perioperative scenarios to examine how consistent respondents were with their stated routine preoperative practice. Clinicians with an academic interest in perioperative medicine were primarily targeted between July and September 2017. STROBE guidelines for observational research and ANZCA Trials Group Survey Reporting recommendations were adhered to.Results194 responses were received, primarily from clinicians practicing in the UK. A similar minority of respondents continue ACEi (n = 57; 30%) and ARBs (n = 62; 32%) throughout the perioperative period. However, timing of preoperative cessation was highly variable, and rarely influenced by the pharmacokinetics of individual ACE-i/ARBs. Respondents’ stated routine practice was frequently misaligned with their management of common pre- and postoperative scenarios involving continuation or restarting ACE-i/ARBs.DiscussionThis survey highlights many inconsistencies amongst clinicians’ practice in perioperative ACE-i/ARB management. Studies designed to reveal an enhanced understanding of perioperative mechanisms at play, coupled with randomised controlled trials, are required to rationally inform the clinical management of ACE-i/ARBs in patients most at risk of postoperative morbidity.
- Published
- 2018
42. In Silico Analysis of Differential Gene Expression in Three Common Rat Models of Diastolic Dysfunction
- Author
-
Raffaele Altara, Fouad A. Zouein, Rita Dias Brandão, Saeed N. Bajestani, Alessandro Cataliotti, George W. Booz, Promovendi CD, RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, and RS: FSE MSP
- Subjects
0301 basic medicine ,lcsh:Diseases of the circulatory (Cardiovascular) system ,medicine.medical_specialty ,hypertension ,Diastole ,heart failure ,Cardiovascular Medicine ,030204 cardiovascular system & hematology ,endothelial and microvascular dysfunction ,03 medical and health sciences ,0302 clinical medicine ,CARDIOMYOCYTE HYPERTROPHY ,Internal medicine ,PRESSURE-OVERLOAD ,EXTRACELLULAR-MATRIX ,medicine ,Myocardial infarction ,CARDIAC-HYPERTROPHY ,SPONTANEOUSLY HYPERTENSIVE-RATS ,Original Research ,Pressure overload ,Cardiotoxicity ,business.industry ,Dilated cardiomyopathy ,metabolic disease ,medicine.disease ,Angiotensin II ,ANGIOTENSIN-II ,030104 developmental biology ,PRESERVED EJECTION FRACTION ,lcsh:RC666-701 ,inflammation ,Heart failure ,CARDIOVASCULAR-DISEASES ,Cardiology ,HEART-FAILURE ,GROWTH-FACTOR RECEPTOR ,Cardiology and Cardiovascular Medicine ,business ,Heart failure with preserved ejection fraction - Abstract
Standard therapies for heart failure with preserved ejection fraction (HFpEF) have been unsuccessful, demonstrating that the contribution of the underlying diastolic dysfunction pathophysiology differs from that of systolic dysfunction in heart failure and currently is far from being understood. Complicating the investigation of HFpEF is the contribution of several comorbidities. Here, we selected three established rat models of diastolic dysfunction defined by three major risk factors associated with HFpEF and researched their commonalities and differences. The top differentially expressed genes in the left ventricle of Dahl salt sensitive (Dahl/SS), spontaneous hypertensive heart failure (SHHF), and diabetes 1 induced HFpEF models were derived from published data in Gene Expression Omnibus and used for a comprehensive interpretation of the underlying pathophysiological context of each model. The diversity of the underlying transcriptomic of the heart of each model is clearly observed by the different panel of top regulated genes: the diabetic model has 20 genes in common with the Dahl/SS and 15 with the SHHF models. Advanced analytics performed in Ingenuity Pathway Analysis (IPA (R)) revealed that Dahl/SS heart tissue transcripts triggered by upstream regulators lead to dilated cardiomyopathy, hypertrophy of heart, arrhythmia, and failure of heart. In the heart of SHHF, a total of 26 genes were closely linked to cardiovascular disease including cardiotoxicity, pericarditis, ST-elevated myocardial infarction, and dilated cardiomyopathy. IPA Upstream Regulator analyses revealed that protection of cardiomyocytes is hampered by inhibition of the ERBB2 plasma membrane-bound receptor tyrosine kinases. Cardioprotective markers such as natriuretic peptide A (NPPA), heat shock 27 kDa protein 1 (HSPB1), and angiogenin (ANG) were upregulated in the diabetes 1 induced model; however, the model showed a different underlying mechanism with a majority of the regulated genes involved in metabolic disorders. In conclusion, our findings suggest that multiple mechanisms may contribute to diastolic dysfunction and HFpEF, and thus drug therapies may need to be guided more by phenotypic characteristics of the cardiac remodeling events than by the underlying molecular processes.
- Published
- 2018
43. Beyond TGFβ
- Author
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K. Kumawat, Janette K. Burgess, C.E. Boorsma, Jaineeta Richardson, Bart G. J. Dekkers, E.M. van Dijk, Alison E. John, Nanomedicine & Drug Targeting, and Molecular Pharmacology
- Subjects
Pulmonary and Respiratory Medicine ,TRANSFORMING GROWTH-FACTOR-BETA-1 ,Pathology ,medicine.medical_specialty ,Pulmonary Fibrosis ,SMOOTH-MUSCLE-CELLS ,TISSUE GROWTH-FACTOR ,EXTRACELLULAR-MATRIX PRODUCTION ,Pathogenesis ,Idiopathic pulmonary fibrosis ,Transforming Growth Factor beta ,Fibrosis ,Parenchyma ,medicine ,Animals ,Humans ,COPD ,Pharmacology (medical) ,Epithelial–mesenchymal transition ,WNT1-INDUCIBLE SIGNALING PROTEIN-1 ,Lung ,PROTEASE-ACTIVATED RECEPTOR-1 ,business.industry ,Biochemistry (medical) ,INDUCED LUNG FIBROSIS ,respiratory system ,medicine.disease ,Angiotensin II ,EPITHELIAL-MESENCHYMAL TRANSITION ,Asthma ,respiratory tract diseases ,Airway ,ANGIOTENSIN-II ,IPF ,Immunology ,Airway Remodeling ,IDIOPATHIC PULMONARY-FIBROSIS ,business ,Signal Transduction - Abstract
Within the lungs, fibrosis can affect both the parenchyma and the airways. Fibrosis is a hallmark pathological change in the parenchyma in patients with idiopathic pulmonary fibrosis (IPF), whilst in asthma or chronic obstructive pulmonary disease (COPD) fibrosis is a component of the remodelling of the airways. In the past decade, significant advances have been made in understanding the disease behaviour and pathogenesis of parenchymal and airway fibrosis and as a result a variety of novel therapeutic targets for slowing or preventing progression of these fibrotic changes have been identified. This review highlights a number of these targets and discusses the potential for treating parenchymal or airway fibrosis through these mediators/pathways in the future.
- Published
- 2014
44. Cathepsin G activity lowers plasma LDL and reduces atherosclerosis
- Author
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Peter Libby, Petri T. Kovanen, Adam Lesner, Katariina Öörni, Jing Wang, Blandine Secco, Tingting Tang, Sara Sjöberg, Cleverson Rodrigues Fernandes, Wenxue Wu, Viviane Tia, Cong-Lin Liu, Xiang Cheng, Guo-Ping Shi, and Galina K. Sukhova
- Subjects
medicine.medical_specialty ,Cathepsin G ,Triglyceride ,Cholesterol ,Low-density lipoprotein ,Biology ,Atherosclerosis ,Angiotensin II ,Article ,Elastin ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Internal medicine ,LDL receptor ,Angiotensin-II ,medicine ,biology.protein ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Molecular Biology ,Lipoprotein - Abstract
Cathepsin G (CatG), a serine protease present in mast cells and neutrophils, can produce angiotensin-II (Ang-II) and degrade elastin. Here we demonstrate increased CatG expression in smooth muscle cells (SMCs), endothelial cells (ECs), macrophages, and T cells from human atherosclerotic lesions. In low-density lipoprotein (LDL) receptor-deficient (Ldlr–/–) mice, the absence of CatG reduces arterial wall elastin degradation and attenuates early atherosclerosis when mice consume a Western diet for 3months. When mice consume this diet for 6months, however, CatG deficiency exacerbates atherosclerosis in aortic arch without affecting lesion inflammatory cell content or extracellular matrix accumulation, but raises plasma total cholesterol and LDL levels without affecting high-density lipoprotein (HDL) or triglyceride levels. Patients with atherosclerosis also have significantly reduced plasma CatG levels that correlate inversely with total cholesterol (r=–0.535, P
- Published
- 2014
45. Obligatory Role of Intraluminal O2− in Acute Endothelin-1 and Angiotensin II Signaling to Mediate Endothelial Dysfunction and MAPK Activation in Guinea-Pig Hearts
- Author
-
Anna Konior, Emilia Wojtera, Andrzej Beresewicz, and Natalia Fedoryszak-Kuśka
- Subjects
Cytoplasm ,endothelial dysfunction ,lcsh:Chemistry ,chemistry.chemical_compound ,Tezosentan ,oxidative stress ,Phosphorylation ,lcsh:QH301-705.5 ,Spectroscopy ,Protein Kinase C ,Mitogen-Activated Protein Kinase 1 ,NADPH oxidase ,biology ,Angiotensin II ,Heart ,General Medicine ,Computer Science Applications ,mitochondria ,guinea-pig heart ,endothelin-1 ,cardiovascular system ,NADPH-oxidase ,medicine.drug ,Signal Transduction ,medicine.medical_specialty ,Guinea Pigs ,Catalysis ,Article ,Inorganic Chemistry ,Oxygen Consumption ,Internal medicine ,medicine ,Diazoxide ,Animals ,Physical and Theoretical Chemistry ,Xanthine oxidase ,Molecular Biology ,angiotensin-II ,Superoxide Dismutase ,Myocardium ,Organic Chemistry ,NADPH Oxidases ,Endothelin 1 ,Endocrinology ,Chelerythrine ,chemistry ,lcsh:Biology (General) ,lcsh:QD1-999 ,mitogen-activated protein kinases ,Apocynin ,biology.protein ,Endothelium, Vascular ,Reactive Oxygen Species ,xanthine oxidase - Abstract
We hypothesized that, due to a cross-talk between cytoplasmic O2−-sources and intraluminally expressed xanthine oxidase (XO), intraluminal O2− is instrumental in mediating intraluminal (endothelial dysfunction) and cytosolic (p38 and ERK1/2 MAPKs phosphorylation) manifestations of vascular oxidative stress induced by endothelin-1 (ET-1) and angiotensin II (AT-II). Isolated guinea-pig hearts were subjected to 10-min agonist perfusion causing a burst of an intraluminal O2−. ET-1 antagonist, tezosentan, attenuated AT-II-mediated O2−, indicating its partial ET-1 mediation. ET-1 and Ang-T (AT-II + tezosentan) triggered intraluminal O2−, endothelial dysfunction, MAPKs and p47phox phosphorylation, and NADPH oxidase (Nox) and XO activation. These effects were: (i) prevented by blocking PKC (chelerythrine), Nox (apocynin), mitochondrial ATP-dependent K+ channel (5-HD), complex II (TTFA), and XO (allopurinol), (ii) mimicked by the activation of Nox (NADH), and mitochondria (diazoxide, 3-NPA) and (iii) the effects by NADH were prevented by 5-HD, TTFA and chelerythrine, and those by diazoxide and 3-NPA by apocynin and chelerythrine, suggesting that the agonists coactivate Nox and mitochondria, which further amplify their activity via PKC. The effects by ET-1, Ang-T, NADH, diazoxide, and 3-NPA were opposed by blocking intraluminal O2− (SOD) and XO, and were mimicked by XO activation (hypoxanthine). Apocynin, TTFA, chelerythrine, and SOD opposed the effects by hypoxanthine. In conclusion, oxidative stress by agonists involves cellular inside-out and outside-in signaling in which Nox-mitochondria-PKC system and XO mutually maintain their activities via the intraluminal O2−.
- Published
- 2014
46. Elastase-2 knockout mice display anxiogenic‐ and antidepressant-like phenotype: putative role for BDNF metabolism in prefrontal cortex
- Author
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Cassiano R.A.F. Diniz, Plinio C. Casarotto, Maria Cristina O. Salgado, Francisco Silveira Guimarães, Leonardo B. M. Resstel, Caroline Biojone, H C Salgado, Sâmia R.L. Joca, Angelina Lesnikova, Eero Castrén, Christiane Becari, Neuroscience Center, Helsinki In Vivo Animal Imaging Platform (HAIP), and Eero Castren / Principal Investigator
- Subjects
Male ,0301 basic medicine ,Elastase-2 ,Hippocampus ,Anxiety ,ANXIETY-LIKE BEHAVIOR ,Marble burying ,0302 clinical medicine ,Conditioning, Psychological ,II TYPE-2 RECEPTOR ,Fear conditioning ,Prefrontal cortex ,RNA MENSAGEIRO ,Mice, Knockout ,0303 health sciences ,Behavior, Animal ,Depression ,Chemistry ,Serine Endopeptidases ,Fear ,PARACELLULAR PERMEABILITY ,Antidepressive Agents ,Recombinant Proteins ,ANGIOTENSIN-II ,Phenotype ,Neurology ,CAPTOPRIL ,Female ,FORMING ENZYME ,RAT ELASTASE-2 ,EXPRESSION ,medicine.medical_specialty ,Elevated plus maze ,Neuroscience (miscellaneous) ,Prefrontal Cortex ,Cellular and Molecular Neuroscience ,03 medical and health sciences ,Internal medicine ,Journal Article ,medicine ,Animals ,Computer Simulation ,RNA, Messenger ,030304 developmental biology ,Brain-derived neurotrophic factor ,Brain-Derived Neurotrophic Factor ,3112 Neurosciences ,MAJOR DEPRESSION ,Angiotensin II ,Mice, Inbred C57BL ,Freezing behavior ,BDNF ,030104 developmental biology ,Endocrinology ,Anxiogenic ,030217 neurology & neurosurgery ,NEUROTROPHIC FACTOR - Abstract
Several pieces of evidence indicate that elastase-2 (ELA2; chymotrypsin-like ELA2) is an alternative pathway to the generation of angiotensin II (ANG II). Elastase-2 knockout mice (ELA2KO) exhibit alterations in the arterial blood pressure and heart rate. However, there is no data on the behavioral consequences of ELA2 deletion. In this study we addressed this question, submitting ELA2KO and wild-type (WT) mice to several models sensitive to anxiety‐ and depression-like, memory, and repetitive behaviors. Our data indicates a higher incidence of barbering behavior in ELA2KO compared to WT, as well as an anxiogenic phenotype, evaluated in the elevated plus maze (EPM). While a decrease in locomotor activity was observed in ELA2KO in EPM, this feature was not the main source of variation in the other parameters analyzed. The marble burying test (MBT) indicated increase in repetitive behavior, observed by a higher number of buried marbles. The actimeter test indicated a decrease in total activity and confirmed the increase in repetitive behavior. The spatial memory was tested by repeated exposure to the actimeter in a 24h interval. Both ELA2KO and WT exhibited decreased activity compared to the first exposure, without any distinction between the genotypes. However, when submitted to the cued fear conditioning, ELA2KO displayed lower levels of freezing behavior in the extinction session when compared to WT, but no difference was observed during the conditioning phase. Increased levels of BDNF were found in the prefrontal cortex but not in the hippocampus of ELA2KO mice compared to WT. Finally, in silico analysis indicates that ELA2 is putatively able to cleave BDNF, and incubation of the purified enzyme with BDNF led to the degradation of the later. Our data suggested an anxiogenic‐ and antidepressant-like phenotype of ELA2KO, possibly associated with increased levels of BDNF in the prefrontal cortex.
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- 2017
47. Concomitant Obesity and Metabolic Syndrome Add to the Atrial Arrhythmogenic Phenotype in Male Hypertensive Rats
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Prashanthan Sanders, Benedikt Linz, Michael Böhm, Rajiv Mahajan, Dominik Linz, Ulrich Schotten, Dennis H. Lau, Mathias Hohl, Andreas Müller, Adrian D. Elliott, Jeroen M.L. Hendriks, Fysiologie, and RS: CARIM - R2.11 - Experimental atrial fibrillation
- Subjects
Male ,0301 basic medicine ,obesity ,medicine.medical_treatment ,030204 cardiovascular system & hematology ,Impaired glucose tolerance ,0302 clinical medicine ,Rats, Inbred SHR ,OSTEOPONTIN ,Arrhythmia and Electrophysiology ,atrial fibrillation ,Original Research ,CATHETER ABLATION ,Atrial fibrillation ,ANGIOTENSIN-II ,Phenotype ,ADIPOSE-TISSUE ,cardiovascular system ,Cardiology ,HEART-FAILURE ,FIBRILLATION ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,SODIUM-ABSORPTION ,circulatory and respiratory physiology ,medicine.medical_specialty ,hypertension ,INHIBITION ,Catheter ablation ,metabolic syndrome ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,Heart Atria ,cardiovascular diseases ,CARDIAC FIBROSIS ,PERICARDIAL FAT ,Fibrillation ,business.industry ,medicine.disease ,Angiotensin II ,Rats ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Animal Models of Human Disease ,Heart failure ,Metabolic syndrome ,business ,Dyslipidemia - Abstract
Background Besides hypertension, obesity and the metabolic syndrome have recently emerged as risk factors for atrial fibrillation. This study sought to delineate the development of an arrhythmogenic substrate for atrial fibrillation in hypertension with and without concomitant obesity and metabolic syndrome. Methods and Results We compared obese spontaneously hypertensive rats ( SHR ‐obese, n=7–10) with lean hypertensive controls ( SHR ‐lean, n=7–10) and normotensive rats (n=7–10). Left atrial emptying function (MRI) and electrophysiological parameters were characterized before the hearts were harvested for histological and biochemical analyses. At the age of 38 weeks, SHR ‐obese, but not SHR ‐lean, showed increased body weight and impaired glucose tolerance together with dyslipidemia compared with normotensive rats. Mean blood pressure was similarly increased in SHR ‐lean and SHR ‐obese when compared with normotensive rats (178±9 and 180±8 mm Hg [not significant] versus 118±5 mm Hg, P SHR ‐obese than in SHR ‐lean. Impairment of left atrial emptying function, increase in total atrial activation time, and conduction heterogeneity, as well as prolongation of inducible atrial fibrillation durations, were more pronounced in SHR ‐obese as compared with SHR ‐lean. Histological and biochemical examinations revealed enhanced triglycerides and more pronounced fibrosis in the left atrium of SHR ‐obese. Besides increased expression of profibrotic markers in SHR ‐lean and SHR ‐obese, the profibrotic extracellular matrix protein osteopontin was highly upregulated only in SHR ‐obese. Conclusions In addition to hypertension alone, concomitant obesity and metabolic syndrome add to the atrial arrhythmogenic phenotype by impaired left atrial emptying function, local conduction abnormalities, interstitial atrial fibrosis formation, and increased propensity for atrial fibrillation.
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- 2017
48. Response of Renal Podocytes to Excessive Hydrostatic Pressure: a Pathophysiologic Cascade in a Malignant Hypertension Model
- Author
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Moshe Stark, Shai Efrati, Sylvia Berman, Fadia Hasan, Keren Doenyas-Barak, Yafit Hachmo, and Ramzia Abu Hamad
- Subjects
lcsh:Diseases of the circulatory (Cardiovascular) system ,Hydrostatic pressure ,030232 urology & nephrology ,Apoptosis ,030204 cardiovascular system & hematology ,lcsh:RC870-923 ,Podocyte ,Hypertension, Malignant ,Transforming Growth Factor beta1 ,03 medical and health sciences ,Paracrine signalling ,0302 clinical medicine ,Podocin ,Paracrine Communication ,lcsh:Dermatology ,medicine ,Cell Adhesion ,Hydrostatic Pressure ,Animals ,Autocrine signalling ,Integrinβ1 ,Mesangial cell ,biology ,Chemistry ,Podocytes ,Glomerular basement membrane ,Angiotensin II ,TGFβ1 ,Detachment/loss of viable podocytes ,General Medicine ,lcsh:RL1-803 ,lcsh:Diseases of the genitourinary system. Urology ,Cell biology ,Rats ,Autocrine Communication ,medicine.anatomical_structure ,lcsh:RC666-701 ,Nephrology ,Mesangial Cells ,Angiotensin-II ,biology.protein ,Cardiology and Cardiovascular Medicine - Abstract
Background/Aims: Renal injuries induced by increased intra-glomerular pressure coincide with podocyte detachment from the glomerular basement membrane (GBM). In previous studies, it was demonstrated that mesangial cells have a crucial role in the pathogenesis of malignant hypertension. However, the exact pathophysiological cascade responsible for podocyte detachment and its relationship with mesangial cells has not been fully elucidated yet and this was the aim of the current study. Methods: Rat renal mesangial or podocytes were exposed to high hydrostatic pressure in an in-vitro model of malignant hypertension. The resulted effects on podocyte detachment, apoptosis and expression of podocin and integrinβ1 in addition to Angiotensin-II and TGF-β1 generation were evaluated. To simulate the paracrine effect podocytes were placed in mesangial cell media pre-exposed to pressure, or in media enriched with Angiotensin-II, TGF-β1 or receptor blockers. Results: High pressure resulted in increased Angiotensin-II levels in mesangial and podocyte cells. Angiotensin-II via the AT1 receptors reduced podocin expression and integrinβ1, culminating in detachment of both viable and apoptotic podocytes. Mesangial cells exposed to pressure had a greater increase in Angiotensin-II than pressure-exposed podocytes. The massively increased concentration of Angiotensin-II by mesangial cells, together with increased TGF-β1 production, resulted in increased apoptosis and detachment of non-viable apoptotic podocytes. Unlike the direct effect of pressure on podocytes, the mesangial mediated effects were not related to changes in adhesion proteins expression. Conclusions: Hypertension induces podocyte detachment by autocrine and paracrine effects. In a direct response to pressure, podocytes increase Angiotensin-II levels. This leads, via AT1 receptors, to structural changes in adhesion proteins, culminating in viable podocyte detachment. Paracrine effects of hypertension, mediated by mesangial cells, lead to higher levels of both Angiotensin-II and TGF-β1, culminating in apoptosis and detachment of non-viable podocytes.
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- 2017
49. Effects of Direct Renin Blockade on Renal & Systemic Hemodynamics and on RAAS Activity, in Weight Excess and Hypertension
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G. A. Lochorn, H. J. Lambers Heerspink, I. van den Berg-Garrelds, Hiroyuki Kobori, Gozewijn D. Laverman, Gerjan Navis, Arjan J. Kwakernaak, J. H. van Embden Andres, M. A. Klijn, Lodi C.W. Roksnoer, Alexander H. J. Danser, Groningen Kidney Center (GKC), Lifestyle Medicine (LM), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Value, Affordability and Sustainability (VALUE), and Internal Medicine
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Male ,Physiology ,SMOOTH-MUSCLE-CELLS ,lcsh:Medicine ,Hemodynamics ,Blood Pressure ,Angiotensin-Converting Enzyme Inhibitors ,BLOOD-PRESSURE ,030204 cardiovascular system & hematology ,(PRO)RENIN RECEPTOR ,Vascular Medicine ,Biochemistry ,GLOMERULAR-FILTRATION-RATE ,Renin-Angiotensin System ,0302 clinical medicine ,Fumarates ,Ramipril ,INHIBITOR ALISKIREN ,Renin ,Medicine and Health Sciences ,Medicine ,030212 general & internal medicine ,Lipid Hormones ,lcsh:Science ,Aldosterone ,Multidisciplinary ,Cross-Over Studies ,Hematology ,Blood Pressure Monitoring, Ambulatory ,Middle Aged ,DOUBLE-BLIND TRIAL ,Body Fluids ,ANGIOTENSIN-II ,Blood ,COLLECTING DUCT RENIN ,Hypertension ,Kidney Diseases ,Anatomy ,medicine.drug ,Research Article ,Glomerular Filtration Rate ,Mean arterial pressure ,medicine.medical_specialty ,Urology ,Excretion ,Renal function ,Blood Plasma ,Renal Circulation ,03 medical and health sciences ,Double-Blind Method ,Internal medicine ,URINARY RENIN ,Albuminuria ,Humans ,Antihypertensive Agents ,Renal Physiology ,business.industry ,lcsh:R ,Biology and Life Sciences ,Effective renal plasma flow ,Renal System ,Overweight ,Angiotensin II ,Amides ,Hormones ,Filtration fraction ,BODY-MASS INDEX ,Blood pressure ,Endocrinology ,lcsh:Q ,business ,Physiological Processes - Abstract
Aim The combination of weight excess and hypertension significantly contributes to cardiovascular risk and progressive kidney damage. An unfavorable renal hemodynamic profile is thought to contribute to this increased risk and may be ameliorated by direct renin inhibition (DRI). The aim of this trial was to assess the effect of DRI on renal and systemic hemodynamics and on RAAS activity, in men with weight excess and hypertension. Methods A randomized, double-blind, cross-over clinical trial to determine the effect of DRI (aliskiren 300 mg/day), with angiotensin converting enzyme inhibition (ACEi; ramipril 10 mg/day) as a positive control, on renal and systemic hemodynamics, and on RAAS activity (n = 15). Results Mean (SEM) Glomerular filtration rate (101 (5) mL/min/1.73m2) remained unaffected by DRI or ACEi. Effective renal plasma flow (ERPF; 301 (14) mL/min/1.73m2) was increased in response to DRI (320 (14) mL/min/1.73m2, P = 0.012) and ACEi (317 (15) mL/min/1.73m2, P = 0.045). Filtration fraction (FF; 34 (0.8)%) was reduced by DRI only (32 (0.7)%, P = 0.044). Mean arterial pressure (109 (2) mmHg) was reduced by DRI (101 (2) mmHg, P = 0.008) and ACEi (103 (3) mmHg, P = 0.037). RAAS activity was reduced by DRI and ACEi. Albuminuria (20 [9–42] mg/d) was reduced by DRI only (12 [5–28] mg/d, P = 0.030). Conclusions In men with weight excess and hypertension, DRI and ACEi improved renal and systemic hemodynamics. Both DRI and ACEi reduced RAAS activity. Thus, DRI provides effective treatment in weight excess and hypertension. Trial Registration Dutch trial register, registration number: 2532 www.trialregister.nl
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- 2017
50. Increased expression of (pro)renin receptor does not cause hypertension or cardiac and renal fibrosis in mice
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Judith Peters, Michael Schwake, Ulrich Wenzel, Christian Krebs, Geneviève Nguyen, Harry van Goor, Aurelie Contrepas, Sascha Lange, Thorsten Wiech, Erfan Ahadzadeh, Michael Bader, Alva Rosendahl, Gianina Niemann, Rolf A.K. Stahl, Groningen Institute for Organ Transplantation (GIOT), and Groningen Kidney Center (GKC)
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Male ,CHRONIC KIDNEY-DISEASE ,Cardiac fibrosis ,Kidney ,Mice ,Fibrosis ,Renin ,Ventricular Dysfunction ,Renal Insufficiency ,Homozygote ,PRORENIN RECEPTOR ,Up-Regulation ,Proton-Translocating ATPases ,ANGIOTENSIN-II ,medicine.anatomical_structure ,Losartan ,Hypertension ,TRANSGENIC RATS ,Female ,Inflammation Mediators ,medicine.drug ,Heterozygote ,medicine.medical_specialty ,Heart Ventricles ,CLIPPED KIDNEY ,SIGNAL-TRANSDUCTION ,Mice, Inbred Strains ,Mice, Transgenic ,Receptors, Cell Surface ,Biology ,Pathology and Forensic Medicine ,RENIN/PRORENIN RECEPTOR ,Internal medicine ,Renin–angiotensin system ,medicine ,Renal fibrosis ,Albuminuria ,Animals ,Molecular Biology ,Hemizygote ,ATP6AP2 ,Kidney metabolism ,DIABETES-MELLITUS ,Cell Biology ,medicine.disease ,END-ORGAN DAMAGE ,Endocrinology ,PRO RENIN RECEPTOR ,Angiotensin II Type 1 Receptor Blockers - Abstract
Binding of renin and prorenin to the (pro)renin receptor (PRR) increases their enzymatic activity and upregulates the expression of pro-fibrotic genes in vitro. Expression of PRR is increased in the heart and kidney of hypertensive and diabetic animals, but its causative role in organ damage is still unclear. To determine whether increased expression of PRR is sufficient to induce cardiac or renal injury, we generated a mouse that constitutively overexpresses PRR by knocking-in the Atp6ap2/PRR gene in the hprt locus under the control of a CMV immediate early enhancer/chicken beta-actin promoter. Mice were backcrossed in the C57BI/6 and FVB/N strain and studied at the age of 12 months. In spite of a 25- to 80-fold renal and up to 400-fold cardiac increase in Atp6ap2/PRR expression, we found no differences in systolic blood pressure or albuminuria between wild-type and PRR overexpressing littermates. Histological examination did not show any renal or cardiac fibrosis in mutant mice. This was supported by real-time PCR analysis of inflammatory markers as well as of pro-fibrotic genes in the kidney and collagen in cardiac tissue. To determine whether the concomitant increase of renin would trigger fibrosis, we treated PRR overexpressing mice with the angiotensin receptor-1 blocker losartan over a period of 6 weeks. Renin expression increased eightfold in the kidney but no renal injury could be detected. In conclusion, our results suggest no major role for PRR in organ damage per se or related to its function as a receptor of renin.
- Published
- 2014
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