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2. The transCampus metabolic training programme explores the link of SARS-CoV-2 virus to metabolic disease

Author

Bornstein, S.R., Guan, K., Brunßen, C., Mueller, G., Kamvissi-Lorenz, V., Lechler, R., Trembath, R., Mayr, M., Poston, L., Sancho, R., Ahmed, S., Alfar, E., Aljani, B., Alves, T.C., Amiel, S., Andoniadou, C.L., Bandral, M., Belavgeni, A., Berger, I., Birkenfeld, A.L., Bonifacio, E., Chavakis, T., Chawla, P., Choudhary, P., Cujba, A.M., Delgadillo Silva, L.F., Demcollari, T., Drotar, D.M., Duin, S., El-Agroudy, N.N., El-Armouche, A., Eugster, A., Gado, M., Gavalas, A., Gelinsky, M., Guirgus, M., Hansen, S., Hanton, E., Hasse, M., Henneicke, H., Heller, C., Hempel, H., Hogstrand, C., Hopkins, D., Jarc, L., Jones, P.M., Kamel, M., Kämmerer, S., King, A.J.F., Kurzbach, A., Lambert, C., Latunde-Dada, Y., Lieberam, I., Liers, J., Li, J.W., Linkermann, A., Locke, S., Ludwig, B., Manea, T., Maremonti, F., Marinicova, Z., McGowan, B.M., Mickunas, M., Mingrone, G., Mohanraj, K., Morawietz, H., Ninov, N., Peakman, M., Persaud, S.J., Pietzsch, J., Cachorro, E., Pullen, T.J., Pyrina, I., Rubino, F., Santambrogio, A., Schepp, F., Schlinkert, P., Scriba, L.D., Siow, R., Solimena, M., Spagnoli, F.M., Speier, S., Stavridou, A., Steenblock, C., Strano, A., Taylor, P., Tiepner, A., Tonnus, W., Tree, T., Watt, F.E., Werdermann, M., Wilson, M., Yusuf, N., and Ziegler, C.G.

Subjects
0301 basic medicine, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Clinical Biochemistry, education, MEDLINE, Disease, Settore MED/17 - MALATTIE INFETTIVE, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, Pandemic, Diabetes Mellitus, medicine, Humans, Obesity, Metabolic disease, Pandemics, metabolic training programme, Medical education, Communicable disease, Scope (project management), SARS-CoV-2, Biochemistry (medical), COVID-19, General Medicine, 030104 developmental biology, Infectious disease (medical specialty), transCampus, Education, Medical, Continuing, Covid-19, Metabolic Training Programme, Transcampus, 030217 neurology & neurosurgery
Abstract

Currently, we are experiencing a true pandemic of a communicable disease by the virus SARS-CoV-2 holding the whole world firmly in its grasp. Amazingly and unfortunately, this virus uses a metabolic and endocrine pathway via ACE2 to enter our cells causing damage and disease. Our international research training programme funded by the German Research Foundation has a clear mission to train the best students wherever they may come from to learn to tackle the enormous challenges of diabetes and its complications for our society. A modern training programme in diabetes and metabolism does not only involve a thorough understanding of classical physiology, biology and clinical diabetology but has to bring together an interdisciplinary team. With the arrival of the coronavirus pandemic, this prestigious and unique metabolic training programme is facing new challenges but also new opportunities. The consortium of the training programme has recognized early on the need for a guidance and for practical recommendations to cope with the COVID-19 pandemic for the community of patients with metabolic disease, obesity and diabetes. This involves the optimal management from surgical obesity programmes to medications and insulin replacement. We also established a global registry analyzing the dimension and role of metabolic disease including new onset diabetes potentially triggered by the virus. We have involved experts of infectious disease and virology to our faculty with this metabolic training programme to offer the full breadth and scope of expertise needed to meet these scientific challenges. We have all learned that this pandemic does not respect or heed any national borders and that we have to work together as a global community. We believe that this transCampus metabolic training programme provides a prime example how an international team of established experts in the field of metabolism can work together with students from all over the world to address a new pandemic.Currently, we are experiencing a true pandemic of a communicable disease by the virus SARS-CoV-2 holding the whole world firmly in its grasp. Amazingly and unfortunately, this virus uses a metabolic and endocrine pathway via ACE2 to enter our cells causing damage and disease. Our international research training programme funded by the German Research Foundation has a clear mission to train the best students wherever they may come from to learn to tackle the enormous challenges of diabetes and its complications for our society. A modern training programme in diabetes and metabolism does not only involve a thorough understanding of classical physiology, biology and clinical diabetology but has to bring together an interdisciplinary team. With the arrival of the coronavirus pandemic, this prestigious and unique metabolic training programme is facing new challenges but also new opportunities. The consortium of the training programme has recognized early on the need for a guidance and for practical recommendations to cope with the COVID-19 pandemic for the community of patients with metabolic disease, obesity and diabetes. This involves the optimal management from surgical obesity programmes to medications and insulin replacement. We also established a global registry analyzing the dimension and role of metabolic disease including new onset diabetes potentially triggered by the virus. We have involved experts of infectious disease and virology to our faculty with this metabolic training programme to offer the full breadth and scope of expertise needed to meet these scientific challenges. We have all learned that this pandemic does not respect or heed any national borders and that we have to work together as a global community. We believe that this transCampus metabolic training programme provides a prime example how an international team of established experts in the field of metabolism can work together with students from all over the world to address a new pandemic.

Published
2021

14. P6286Interaction between oxidized LDL, angiotensin II and oxidative stress

Author

Catar, R.A., primary, Goettsch, C., additional, Taye, A., additional, Hofmann, A., additional, Brunssen, C., additional, Muller, G., additional, Shahid, A., additional, Lehmann, S., additional, Schubert, U., additional, Ludwig, B., additional, Ziegler, C.G., additional, Bornstein, S.R., additional, Krug, A.W., additional, Walther, T., additional, and Morawietz, H., additional

Published
2017
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15. The transCampus Metabolic Training Programme Explores the Link of SARS-CoV-2 Virus to Metabolic Disease.

Author

Bornstein, S. R., Guan, K., Brunßen, C., Mueller, G., Kamvissi-Lorenz, V., Lechler, R., Trembath, R., Mayr, M., Poston, L., Sancho, R., Ahmed, S., Alfar, E., Aljani, B., Alves, T. C., Amiel, S., Andoniadou, C. L., Bandral, M., Belavgeni, A., Berger, I., and Birkenfeld, A.

Abstract

Copyright of Hormone & Metabolic Research is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2021
Full Text
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16. Poster session 3Cell growth, differentiation and stem cells - Heart511The role of the endocannabinoid system in modelling muscular dystrophy cardiac disease with induced pluripotent stem cells.512An emerging role of T lymphocytes in cardiac regenerative processes in heart failure due to dilated cardiomyopathy513Canonical wnt signaling reverses the ‘aged/senescent’ human endogenous cardiac stem cell phenotype514Hippo signalling modulates survival of human induced pluripotent stem cell-derived cardiomyocytes515Biocompatibility of mesenchymal stem cells with a spider silk matrix and its potential use as scaffold for cardiac tissue regeneration516A snapshot of genome-wide transcription in human induced pluripotent stem cell-derived hepatocyte-like cells (iPSC-HLCs)517Can NOS/sGC/cGK1 pathway trigger the differentiation and maturation of mouse embryonic stem cells (ESCs)?518Introduction of external Ik1 to human-induced pluripotent stem cell-derived cardiomyocytes via Ik1-expressing HEK293519Cell therapy of the heart studied using adult myocardial slices in vitro520Enhancement of the paracrine potential of human adipose derived stem cells when cultured as spheroid bodies521Mechanosensitivity of cardiomyocyte progenitor cells: the strain response in 2D and 3D environments522The effect of the vascular-like network on the maturation of the human induced pluripotent stem cell derived cardiomyocytes.Transcriptional control and RNA species - Heart525Gene expression regulation in heart failure: from pathobiology to bioinformatics526Human transcriptome in idiopathic dilated cardiomyopathy - a novel high throughput screening527A high-throghput approach unveils putative miRNA-mediated mitochondria-targeted cardioprotective circuits activated by T3 in the post ischemia reperfusion setting528The effect of uraemia on the expression of miR-212/132 and the calcineurin pathway in the rat heartCytokines and cellular inflammation - Heart531Lack of growth differentiation factor 15 aggravates adverse cardiac remodeling upon pressure-overload in mice532Blocking heteromerization of platelet chemokines ccl5 and cxcl4 reduces inflammation and preserves heart function after myocardial infarction533Is there an association between low-dose aspirin use and clinical outcome in HFPEF? Implications of modulating monocyte function and inflammatory mediator release534N-terminal truncated intracellular matrix metalloproteinase-2 expression in diabetic heart.535Expression of CD39 and CD73 on peripheral T-cell subsets in calcific aortic stenosis536Mast cells in the atrial myocardium of patients with atrial fibrillation: a comparison with patients in sinus rhythm539Characteristics of the inflammatory response in patients with coronary artery disease and arterial hypertension540Pro-inflammatory cytokines as cardiovascular events predictors in rheumatoid arthritis and asymptomatic atherosclerosis541Characterization of FVB/N murinic bone marrow-derived macrophage polarization into M1 and M2 phenotypes542The biological expression and thoracic anterior pain syndromeSignal transduction - Heart545The association of heat shock protein 90 and TGFbeta receptor I is involved in collagen production during cardiac remodelling in aortic-banded mice546Loss of the inhibitory GalphaO protein in the rostral ventrolateral medulla of the brainstem leads to abnormalities in cardiovascular reflexes and altered ventricular excitablitiy547Selenoprotein P regulates pressure overload-induced cardiac remodeling548Study of adenylyl cyclase activity in erythrocyte membranes in patients with chronic heart failure549Direct thrombin inhibitors inhibit atrial myocardium hypertrophy in a rat model of heart failure and atrial remodeling550Tissue factor / FVIIa transactivates the IGF-1R by a Src-dependent phosphorylation of caveolin-1551Notch signaling is differently altered in endothelial and smooth muscle cells of ascending aortic aneurysm patients552Frizzled 5 expression is essential for endothelial proliferation and migration553Modulation of vascular function and ROS production by novel synthetic benzopyran analogues in diabetes mellitusExtracellular matrix and fibrosis - Heart556Cardiac fibroblasts as inflammatory supporter cells trigger cardiac inflammation in heart failure557A role for galectin-3 in calcific aortic valve stenosis558Omega-3 polyunsaturated fatty acids- can they decrease risk for ventricular fibrillation?559Serum levels of elastin derived peptides and circulating elastin-antielastin immune complexes in sera of patients with coronary artery disease560Endocardial fibroelastosis is secondary to hemodynamic alterations in the chick model of hypoplastic left heart syndrome561Dynamics of serum levels of matrix metalloproteinases in primary anterior STEMI patients564Deletion of the alpha-7 nicotinic acetylcholine receptor changes the vascular remodeling induced by transverse aortic constriction in mice.565Extracellular matrix remodelling in response to venous hypertension: proteomics of human varicose veinsIon channels, ion exchangers and cellular electrophysiology - Heart568Microtubule-associated protein RP/EB family member 1 modulates sodium channel trafficking and cardiac conduction569Investigation of electrophysiological abnormalities in a rabbit athlete's heart model570Upregulation of expression of multiple genes in the atrioventricular node of streptozotocin-induced diabetic rat571miR-1 as a regulator of sinoatrial rhythm in endurance training adaptation572Selective sodium-calcium exchanger inhibition reduces myocardial dysfunction associated with hypokalaemia and ventricular fibrillation573Effect of racemic and levo-methadone on action potential of human ventricular cardiomyocytes574Acute temperature effects on the chick embryonic heart functionVasculogenesis, angiogenesis and arteriogenesis577Clinical improvement and enhanced collateral vessel growth after monocyte transplantation in mice578The role of HIF-1 alpha, VEGF and obstructive sleep apnoea in the development of coronary collateral circulation579Initiating cardiac repair with a trans-coronary sinus catheter intervention in an ischemia/reperfusion porcine animal model580Early adaptation of pre-existing collaterals after acute arteriolar and venular microocclusion: an in vivo study in chick chorioallantoic membraneEndothelium583EDH-type responses to the activator of potassium KCa2.3 and KCa3.1 channels SKA-31 in the small mesenteric artery from spontaneously hypertensive rats584The peculiarities of endothelial dysfunction in patients with chronic renocardial syndrome585Endothelial dysfunction, atherosclerosis of the carotid arteries and level of leptin in patient with coronary heart disease in combination with hepatic steatosis depend from body mass index.586Role of non-coding RNAs in thoracic aortic aneurysm associated with bicuspid aortic valve587Cigarette smoke extract abrogates atheroprotective effects of high laminar flow on endothelial function588The prognostic value of anti-connective tissue antibodies in coronary heart disease and asymptomatic atherosclerosis589Novel potential properties of bioactive peptides from spanish dry-cured ham on the endothelium.Lipids592Intermediate density lipoprotein is associated with monocyte subset distribution in patients with stable atherosclerosis593The characteristics of dyslipidemia in rheumatoid arthritisAtherosclerosis596Macrophages differentiated in vitro are heterogeneous: morphological and functional profile in patients with coronary artery disease597Palmitoylethanolamide promotes anti-inflammatory phenotype of macrophages and attenuates plaque formation in ApoE-/- mice598Amiodarone versus esmolol in the perioperative period: an in vitro study of coronary artery bypass grafts599BMPRII signaling of fibrocytes, a mesenchymal progenitor cell population, is increased in STEMI and dyslipidemia600The characteristics of atherogenesis and systemic inflammation in rheumatoid arthritis601Role of adenosine-to-inosine RNA editing in human atherosclerosis602Presence of bacterial DNA in thrombus aspirates of patients with myocardial infarction603Novel E-selectin binding polymers reduce atherosclerotic lesions in ApoE(-/-) mice604Differential expression of the plasminogen receptor Plg-RKT in monocyte and macrophage subsets - possible functional consequences in atherogenesis605Apelin-13 treatment enhances the stability of atherosclerotic plaques606Mast cells are increased in the media of coronary lesions in patients with myocardial infarction and favor atherosclerotic plaque instability607Association of neutrophil to lymphocyte ratio with presence of isolated coronary artery ectasiaCalcium fluxes and excitation-contraction coupling610The coxsackie- and adenovirus receptor (CAR) regulates calcium homeostasis in the developing heart611HMW-AGEs application acutely reduces ICaL in adult cardiomyocytes612Measuring electrical conductibility of cardiac T-tubular systems613Postnatal development of cardiac excitation-contraction coupling in rats614Role of altered Ca2+ homeostasis during adverse cardiac remodeling after ischemia/reperfusion615Experimental study of sarcoplasmic reticulum dysfunction and energetic metabolism in failing myocardium associated with diabetes mellitusHibernation, stunning and preconditioning618Volatile anesthetic preconditioning attenuates ischemic-reperfusion injury in type II diabetic patients undergoing on-pump heart surgery619The effect of early and delayed phase of remote ischemic preconditioning on ischemia-reperfusion injury in the isolated hearts of healthy and diabetic rats620Post-conditioning with 1668-thioate leads to attenuation of the inflammatory response and remodeling with less fibrosis and better left ventricular function in a murine model of myocardial infarction621Maturation-related changes in response to ischemia-reperfusion injury and in effects of classical ischemic preconditioning and remote preconditioningMitochondria and energetics624Phase changes in myocardial mitochondrial respiration caused by hypoxic preconditioning or periodic hypoxic training625Desmin mutations depress mitochondrial metabolism626Methylene blue modulates mitochondrial function and monoamine oxidases-related ROS production in diabetic rat hearts627Doxorubicin modulates the real-time oxygen consumption rate of freshly isolated adult rat and human ventricular cardiomyocytesCardiomyopathies and fibrosis630Effects of genetic or pharmacologic inhibition of the ubiquitin/proteasome system on myocardial proteostasis and cardiac function631Suppression of Wnt signalling in a desmoglein-2 transgenic mouse model for arrhythmogenic cardiomyopathy632Cold-induced cardiac hypertrophy is reversed after thermo-neutral deacclimatization633CD45 is a sensitive marker to diagnose lymphocytic myocarditis in endomyocardial biopsies of living patients and in autopsies634Atrial epicardial adipose tissue derives from epicardial progenitors635Caloric restriction ameliorates cardiac function, sympathetic cardiac innervation and beta-adrenergic receptor signaling in an experimental model of post-ischemic heart failure636High fat diet improves cardiac remodelling and function after extensive myocardial infarction in mice637Epigenetic therapy reduces cardiac hypertrophy in murine models of heart failure638Imbalance of the VHL/HIF signaling in WT1+ Epicardial Progenitors results in coronary vascular defects, fibrosis and cardiac hypertrophy639Diastolic dysfunction is the first stage of the developing heart failure640Colchicine aggravates coxsackievirus B3 infection in miceArterial and pulmonary hypertension642Osteopontin as a marker of pulmonary hypertension in patients with coronary heart disease combined with chronic obstructive pulmonary disease643Myocardial dynamic stiffness is increased in experimental pulmonary hypertension partly due to incomplete relaxation644Hypotensive effect of quercetin is possibly mediated by down-regulation of immunotroteasome subunits in aorta of spontaneously hypertensive rats645Urocortin-2 improves right ventricular function and attenuates experimental pulmonary arterial hypertension646A preclinical evaluation of the anti-hypertensive properties of an aqueous extract of Agathosma (Buchu)Biomarkers648The adiponectin level in hypertensive females with rheumatoid arthritis and its relationship with subclinical atherosclerosis649Markers for identification of renal dysfunction in the patients with chronic heart failure650cardio-hepatic syndromes in chronic heart failure: North Africa profile651To study other biomarkers that assess during myocardial infarction652Interconnections of apelin levels with parameters of lipid metabolism in hypertension patients653Plasma proteomics in hypertension: prediction and follow-up of albuminuria during chronic renin-angiotensin system suppression654Soluble RAGE levels in plasma of patients with cerebrovascular events

Author

Gowran, A, primary, Kulikova, T, primary, Lewis, FC, primary, Foldes, G, primary, Fuentes, L, primary, Viiri, LE, primary, Spinelli, V, primary, Costa, A, primary, Perbellini, F, primary, Sid-Otmane, C, primary, Bax, NAM, primary, Pekkanen-Mattila, M, primary, Schiano, C, primary, Chaloupka, A, primary, Forini, F, primary, Sarkozy, M, primary, De Jager, SCA, primary, Vajen, T, primary, Glezeva, N, primary, Lee, H W, primary, Golovkin, A, primary, Kucera, T, primary, Musikhina, NA, primary, Korzhenkov, NP, primary, Santuchi, M DE C, primary, Munteanu, D, primary, Garcia, RG, primary, Ang, R, primary, Usui, S, primary, Kamilova, U, primary, Jumeau, C, primary, Aberg, M, primary, Kostina, DA, primary, Brandt, MM, primary, Muntean, D, primary, Lindner, D, primary, Sadaba, R, primary, Bacova, B, primary, Nikolov, A, primary, Sedmera, D, primary, Ryabov, V, primary, Neto, FP, primary, Lynch, M, primary, Portero, V, primary, Kui, P, primary, Howarth, FC, primary, Gualdoni, A, primary, Prorok, J, primary, Diolaiuti, L, primary, Vostarek, F, primary, Wagner, M, primary, Abela, MA, primary, Nebert, C, primary, Xiang, W, primary, Kloza, M, primary, Maslenko, A, primary, Grechanyk, M, primary, Bhattachariya, A, primary, Morawietz, H, primary, Babaeva, AR, primary, Martinez Sanchez, SM, primary, Krychtiuk, KA, primary, Starodubova, J, primary, Fiorelli, S, primary, Rinne, P, primary, Ozkaramanli Gur, D, primary, Hofbauer, T, primary, Stellos, K, primary, Pinon, P, primary, Tsoref, O, primary, Thaler, B, primary, Fraga-Silva, RA, primary, Fuijkschot, WW, primary, Shaaban, MNS, primary, Matthaeus, C, primary, Deluyker, D, primary, Scardigli, M, primary, Zahradnikova, A, primary, Dominguez, A, primary, Kondrat'eva, D, primary, Sosorburam, T, primary, Murarikova, M, primary, Duerr, GD, primary, Griecsova, L, primary, Portnichenko, VI, primary, Smolina, N, primary, Duicu, OANA M, primary, Elder, JM, primary, Zaglia, T, primary, Lorenzon, A, primary, Ruperez, C, primary, Woudstra, L, primary, Suffee, N, primary, De Lucia, C, primary, Russell-Hallinan, A, primary, Menendez-Montes, I, primary, Kapelko, VI, primary, Emmens, RW, primary, Hetman, O, primary, Van Der Laarse, WJ, primary, Goncharov, S, primary, Adao, R, primary, Huisamen, B, primary, Sirenko, O, primary, Nassiri, I, primary, Tserendavaa, SUMIYA, primary, Yushko, K, primary, Baldan Martin, M, primary, Falcone, C, primary, Vigorelli, V, additional, Nigro, P, additional, Pompilio, G, additional, Stepanova, O, additional, Valikhov, M, additional, Samko, A, additional, Masenko, V, additional, Tereschenko, S, additional, Teoh, T, additional, Domenjo-Vila, E, additional, Theologou, T, additional, Field, M, additional, Awad, W, additional, Yasin, M, additional, Nadal-Ginard, B, additional, Ellison-Hughes, GM, additional, Hellen, N, additional, Vittay, O, additional, Harding, SE, additional, Gomez-Cid, L, additional, Fernandez-Santos, ME, additional, Suarez-Sancho, S, additional, Plasencia, V, additional, Climent, A, additional, Sanz-Ruiz, R, additional, Hedhammar, M, additional, Atienza, F, additional, Fernandez-Aviles, F, additional, Kiamehr, M, additional, Oittinen, M, additional, Viiri, KM, additional, Kaikkonen, M, additional, Aalto-Setala, K, additional, Diolaiuti, L, additional, Laurino, A, additional, Sartiani, L, additional, Vona, A, additional, Zanardelli, M, additional, Cerbai, E, additional, Failli, P, additional, Hortigon-Vinagre, MP, additional, Van Der Heyden, M, additional, Burton, FL, additional, Smith, GL, additional, Watson, S, additional, Scigliano, M, additional, Tkach, S, additional, Alayoubi, S, additional, Terracciano, CM, additional, Ly, HQ, additional, Mauretti, A, additional, Van Marion, MH, additional, Van Turnhout, MC, additional, Van Der Schaft, DWJ, additional, Sahlgren, CM, additional, Goumans, MJ, additional, Bouten, CVC, additional, Vuorenpaa, H, additional, Penttinen, K, additional, Sarkanen, R, additional, Ylikomi, T, additional, Heinonen, T, additional, Grimaldi, V, additional, Aprile, M, additional, Esposito, R, additional, Maiello, C, additional, Soricelli, A, additional, Colantuoni, V, additional, Costa, V, additional, Ciccodicola, A, additional, Napoli, C, additional, Rowe, GC, additional, Johnson, K, additional, Arany, ZP, additional, Del Monte, F, additional, D'aurizio, R, additional, Kusmic, C, additional, Nicolini, G, additional, Baumgart, M, additional, Groth, M, additional, Ucciferri, N, additional, Iervasi, G, additional, Pitto, L, additional, Pipicz, M, additional, Gaspar, R, additional, Siska, A, additional, Foldesi, I, additional, Kiss, K, additional, Bencsik, P, additional, Thum, T, additional, Batkai, S, additional, Csont, T, additional, Haan, JJ, additional, Bosch, L, additional, Brans, MAD, additional, Van De Weg, SM, additional, Deddens, JC, additional, Lee, SJ, additional, Sluijter, JPG, additional, Pasterkamp, G, additional, Werner, I, additional, Projahn, D, additional, Staudt, M, additional, Curaj, A, additional, Soenmez, TT, additional, Simsekyilmaz, S, additional, Hackeng, TM, additional, Von Hundelshausen, P, additional, Koenen, RR, additional, Weber, C, additional, Liehn, EA, additional, Santos-Martinez, M, additional, Medina, C, additional, Watson, C, additional, Mcdonald, K, additional, Gilmer, J, additional, Ledwidge, M, additional, Song, SH, additional, Lee, MY, additional, Park, MH, additional, Choi, JC, additional, Ahn, JH, additional, Park, JS, additional, Oh, JH, additional, Choi, JH, additional, Lee, HC, additional, Cha, KS, additional, Hong, TJ, additional, Kudryavtsev, I, additional, Serebryakova, M, additional, Malashicheva, A, additional, Shishkova, A, additional, Zhiduleva, E, additional, Moiseeva, O, additional, Durisova, M, additional, Blaha, M, additional, Melenovsky, V, additional, Pirk, J, additional, Kautzner, J, additional, Petelina, TI, additional, Gapon, LI, additional, Gorbatenko, EA, additional, Potolinskaya, YV, additional, Arkhipova, EV, additional, Solodenkova, KS, additional, Osadchuk, MA, additional, Dutra, MF, additional, Oliveira, FCB, additional, Silva, MM, additional, Passos-Silva, DG, additional, Goncalves, R, additional, Santos, RAS, additional, Da Silva, RF, additional, Gavrilescu, CM, additional, Paraschiv, CM, additional, Manea, P, additional, Strat, LC, additional, Gomez, JMG, additional, Merino, D, additional, Hurle, MA, additional, Nistal, JF, additional, Aires, A, additional, Cortajarena, AL, additional, Villar, AV, additional, Abramowitz, J, additional, Birnbaumer, L, additional, Gourine, AV, additional, Tinker, A, additional, Takamura, M, additional, Takashima, S, additional, Inoue, O, additional, Misu, H, additional, Takamura, T, additional, Kaneko, S, additional, Alieva, TOHIRA, additional, Mougenot, N, additional, Dufilho, M, additional, Hatem, S, additional, Siegbahn, A, additional, Kostina, AS, additional, Uspensky, VE, additional, Moiseeva, OM, additional, Kostareva, AA, additional, Malashicheva, AB, additional, Van Dijk, CGM, additional, Chrifi, I, additional, Verhaar, MC, additional, Duncker, DJ, additional, Cheng, C, additional, Sturza, A, additional, Petrus, A, additional, Duicu, O, additional, Kiss, L, additional, Danila, M, additional, Baczko, I, additional, Jost, N, additional, Gotzhein, F, additional, Schon, J, additional, Schwarzl, M, additional, Hinrichs, S, additional, Blankenberg, S, additional, Volker, U, additional, Hammer, E, additional, Westermann, D, additional, Martinez-Martinez, E, additional, Arrieta, V, additional, Fernandez-Celis, A, additional, Jimenez-Alfaro, L, additional, Melero, A, additional, Alvarez-Asiain, V, additional, Cachofeiro, V, additional, Lopez-Andres, N, additional, Tribulova, N, additional, Wallukat, G, additional, Knezl, V, additional, Radosinska, J, additional, Barancik, M, additional, Tsinlikov, I, additional, Tsinlikova, I, additional, Nicoloff, G, additional, Blazhev, A, additional, Pesevski, Z, additional, Kvasilova, A, additional, Stopkova, T, additional, Eckhardt, A, additional, Buffinton, C M, additional, Nanka, O, additional, Kercheva, M, additional, Suslova, T, additional, Gusakova, A, additional, Ryabova, T, additional, Markov, V, additional, Karpov, R, additional, Seemann, H, additional, Alcantara, TC, additional, Santuchi, M DE C, additional, Fonseca, SG, additional, Barallobre-Barreiro, J, additional, Oklu, R, additional, Fava, M, additional, Baig, F, additional, Yin, X, additional, Albadawi, H, additional, Jahangiri, M, additional, Stoughton, J, additional, Mayr, M, additional, Podliesna, SP, additional, Veerman, CCV, additional, Verkerk, AOV, additional, Klerk, MK, additional, Lodder, EML, additional, Mengarelli, IM, additional, Bezzina, CRB, additional, Remme, CAR, additional, Takacs, H, additional, Polyak, A, additional, Morvay, N, additional, Lepran, I, additional, Tiszlavicz, L, additional, Nagy, N, additional, Ordog, B, additional, Farkas, A, additional, Forster, T, additional, Varro, A, additional, Farkas, AS, additional, Jayaprakash, P, additional, Parekh, K, additional, Ferdous, Z, additional, Oz, M, additional, Dobrzynski, H, additional, Adrian, TE, additional, Landi, S, additional, Bonzanni, M, additional, D'souza, A, additional, Boyett, M, additional, Bucchi, A, additional, Baruscotti, M, additional, Difrancesco, D, additional, Barbuti, A, additional, Kui, P, additional, Oravecz, K, additional, Hezso, T, additional, Levijoki, J, additional, Pollesello, P, additional, Koskelainen, T, additional, Otsomaa, L, additional, Farkas, A S, additional, Papp, JGY, additional, Toth, A, additional, Acsai, K, additional, Dini, L, additional, Mazzoni, L, additional, Mugelli, A, additional, Svatunkova, J, additional, Sedmera, D, additional, Deffge, C, additional, Baer, C, additional, Weinert, S, additional, Braun-Dullaeus, RC, additional, Herold, J, additional, Cassar, AC, additional, Zahra, GZ, additional, Pllaha, EP, additional, Dingli, PD, additional, Montefort, SM, additional, Xuereb, RGX, additional, Aschacher, T, additional, Messner, B, additional, Eichmair, E, additional, Mohl, W, additional, Reglin, B, additional, Rong, W, additional, Nitzsche, B, additional, Maibier, M, additional, Guimaraes, P, additional, Ruggeri, A, additional, Secomb, TW, additional, Pries, AR, additional, Baranowska-Kuczko, M, additional, Karpinska, O, additional, Kusaczuk, M, additional, Malinowska, B, additional, Kozlowska, H, additional, Demikhova, N, additional, Vynnychenko, L, additional, Prykhodko, O, additional, Grechanyk, N, additional, Kuryata, A, additional, Cottrill, KA, additional, Du, L, additional, Bjorck, HM, additional, Maleki, S, additional, Franco-Cereceda, A, additional, Chan, SY, additional, Eriksson, P, additional, Giebe, S, additional, Cockcroft, N, additional, Hewitt, K, additional, Brux, M, additional, Brunssen, C, additional, Tarasov, AA, additional, Davidov, SI, additional, Reznikova, EA, additional, Tapia Abellan, A, additional, Angosto Bazarra, D, additional, Pelegrin Vivancos, P, additional, Montoro Garcia, S, additional, Kastl, SP, additional, Pongratz, T, additional, Goliasch, G, additional, Gaspar, L, additional, Maurer, G, additional, Huber, K, additional, Dostal, E, additional, Pfaffenberger, S, additional, Oravec, S, additional, Wojta, J, additional, Speidl, WS, additional, Osipova, I, additional, Sopotova, I, additional, Eligini, S, additional, Cosentino, N, additional, Marenzi, G, additional, Tremoli, E, additional, Rami, M, additional, Ring, L, additional, Steffens, S, additional, Gur, O, additional, Gurkan, S, additional, Mangold, A, additional, Scherz, T, additional, Panzenboeck, A, additional, Staier, N, additional, Heidari, H, additional, Mueller, J, additional, Lang, IM, additional, Gatsiou, A, additional, Stamatelopoulos, K, additional, Perisic, L, additional, John, D, additional, Lunella, FF, additional, Hedin, U, additional, Zeiher, A, additional, Dimmeler, S, additional, Nunez, L, additional, Moure, R, additional, Marron-Linares, G, additional, Flores, X, additional, Aldama, G, additional, Salgado, J, additional, Calvino, R, additional, Tomas, M, additional, Bou, G, additional, Vazquez, N, additional, Hermida-Prieto, M, additional, Vazquez-Rodriguez, JM, additional, Amit, U, additional, Landa, N, additional, Kain, D, additional, Tyomkin, D, additional, David, A, additional, Leor, J, additional, Hohensinner, PJ, additional, Baumgartner, J, additional, Krychtiuk, KA, additional, Baik, N, additional, Miles, LA, additional, Seeman, H, additional, Montecucco, F, additional, Da Silva, AR, additional, Costa-Fraga, FP, additional, Anguenot, L, additional, Mach, FP, additional, Stergiopulos, N, additional, Kupreishvili, K, additional, Vonk, ABA, additional, Smulders, YM, additional, Van Hinsbergh, VWM, additional, Stooker, W, additional, Niessen, HWM, additional, Krijnen, PAJ, additional, Ashmawy, MM, additional, Salama, MA, additional, Elamrosy, MZ, additional, Juettner, R, additional, Rathjen, F G, additional, Bito, V, additional, Crocini, C, additional, Ferrantini, C, additional, Gabbrielli, T, additional, Silvestri, L, additional, Coppini, R, additional, Tesi, C, additional, Poggesi, C, additional, Pavone, FS, additional, Sacconi, L, additional, Mackova, K, additional, Zahradnik, I, additional, Zahradnikova, A, additional, Diaz, I, additional, Sanchez De Rojas De Pedro, E, additional, Hmadcha, K, additional, Calderon Sanchez, E, additional, Benitah, JP, additional, Gomez, AM, additional, Smani, T, additional, Ordonez, A, additional, Afanasiev, SA, additional, Egorova, MV, additional, Popov, SV, additional, Wu Qing, P, additional, Cheng, X, additional, Carnicka, S, additional, Pancza, D, additional, Jasova, M, additional, Kancirova, I, additional, Ferko, M, additional, Ravingerova, T, additional, Wu, S, additional, Schneider, M, additional, Marggraf, V, additional, Verfuerth, L, additional, Frede, S, additional, Boehm, O, additional, Dewald, O, additional, Baumgarten, G, additional, Kim, S-C, additional, Farkasova, V, additional, Gablovsky, I, additional, Bernatova, I, additional, Nosar, V, additional, Portnychenko, A, additional, Drevytska, T, additional, Mankovska, I, additional, Gogvadze, V, additional, Sejersen, T, additional, Kostareva, A, additional, Wolf, A, additional, Privistirescu, A, additional, Muntean, D, additional, O ' Gara, P, additional, Sanchez-Alonso, JL, additional, Lyon, AR, additional, Prando, V, additional, Pianca, N, additional, Lo Verso, F, additional, Milan, G, additional, Pesce, P, additional, Sandri, M, additional, Mongillo, M, additional, Beffagna, G, additional, Poloni, G, additional, Dazzo, E, additional, Sabatelli, P, additional, Doliana, R, additional, Polishchuk, R, additional, Carnevale, D, additional, Lembo, G, additional, Bonaldo, P, additional, Braghetta, P, additional, Rampazzo, A, additional, Cairo, M, additional, Giralt, M, additional, Villarroya, F, additional, Planavila, A, additional, Biesbroek, PS, additional, Emmens, RWE, additional, Juffermans, LJM, additional, Van Der Wall, AC, additional, Van Rossum, AC, additional, Niessen, JWM, additional, Moor Morris, T, additional, Dilanian, G, additional, Farahmand, P, additional, Puceat, M, additional, Gambino, G, additional, Petraglia, L, additional, Elia, A, additional, Komici, K, additional, Femminella, GD, additional, D'amico, ML, additional, Pagano, G, additional, Cannavo, A, additional, Liccardo, D, additional, Koch, WJ, additional, Nolano, M, additional, Leosco, D, additional, Ferrara, N, additional, Rengo, G, additional, Neary, R, additional, Shiels, L, additional, Baugh, J, additional, Palacios, B, additional, Escobar, B, additional, Alonso, AV, additional, Guzman, G, additional, Ruiz-Cabello, J, additional, Jimenez-Borreguero, LJ, additional, Martin-Puig, S, additional, Lakomkin, VL, additional, Lukoshkova, EV, additional, Abramov, AA, additional, Gramovich, VV, additional, Vyborov, ON, additional, Ermishkin, VV, additional, Undrovinas, NA, additional, Shirinsky, VP, additional, Smilde, BJ, additional, Woudstra, L, additional, Fong Hing, G, additional, Wouters, D, additional, Zeerleder, S, additional, Murk, JL, additional, Van Ham, SM, additional, Heymans, S, additional, Krakhmalova, O, additional, Van Groen, D, additional, Bogaards, SJP, additional, Schalij, I, additional, Portnichenko, GV, additional, Tumanovska, LV, additional, Goshovska, YV, additional, Lapikova-Bryhinska, TU, additional, Nagibin, VS, additional, Dosenko, VE, additional, Mendes-Ferreira, P, additional, Maia-Rocha, C, additional, Santos-Ribeiro, D, additional, Potus, F, additional, Breuils-Bonnet, S, additional, Provencher, S, additional, Bonnet, S, additional, Rademaker, M, additional, Leite-Moreira, AF, additional, Bras-Silva, C, additional, Lopes, J, additional, Kuryata, O, additional, Lusynets, T, additional, Alikulov, I, additional, Nourddine, M, additional, Azzouzi, L, additional, Habbal, R, additional, Tserendavaa, SUMIYA, additional, Enkhtaivan, ODKHUU, additional, Shagdar, ZORIGO, additional, Malchinkhuu, MUNKHZ, additional, Malchinkhuu, MUNLHZ, additional, Koval, S, additional, Starchenko, T, additional, Mourino-Alvarez, L, additional, Gonzalez-Calero, L, additional, Sastre-Oliva, T, additional, Lopez, JA, additional, Vazquez, J, additional, Alvarez-Llamas, G, additional, Ruilope, LUIS M, additional, De La Cuesta, F, additional, Barderas, MG, additional, Bozzini, S, additional, D'angelo, A, additional, and Pelissero, G, additional

Published
2016
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17. Increased Gene Expression of the Cardiac Endothelin System in Obese Mice

Author

Catar, R., additional, Muller, G., additional, Brandt, A., additional, Langbein, H., additional, Brunssen, C., additional, Goettsch, C., additional, Frenzel, A., additional, Hofmann, A., additional, Goettsch, W., additional, Steinbronn, N., additional, Strasser, R., additional, Schubert, U., additional, Ludwig, B., additional, Bornstein, S., additional, and Morawietz, H., additional

Published
2014
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21. Poster session 3

Author

Nanka, O., primary, Krejci, E., additional, Pesevski, Z., additional, Sedmera, D., additional, Smart, N., additional, Rossdeutsch, A., additional, Dube, K. N., additional, Riegler, J., additional, Price, A. N., additional, Taylor, A., additional, Muthurangu, V., additional, Turner, M., additional, Lythgoe, M. F., additional, Riley, P. R., additional, Kryvorot, S., additional, Vladimirskaya, T., additional, Shved, I., additional, Schwarzl, M., additional, Seiler, S., additional, Huber, S., additional, Steendijk, P., additional, Maechler, H., additional, Truschnig-Wilders, M., additional, Pieske, B., additional, Post, H., additional, Caprio, C., additional, Baldini, A., additional, Chiavacci, E., additional, Dolfi, L., additional, Verduci, L., additional, Meghini, F., additional, Cremisi, F., additional, Pitto, L., additional, Kuan, T.-C., additional, Chen, M.-C., additional, Yang, T.-H., additional, Wu, W.-T., additional, Lin, C. S., additional, Rai, H., additional, Kumar, S., additional, Sharma, A. K., additional, Mastana, S., additional, Kapoor, A., additional, Pandey, C. M., additional, Agrawal, S., additional, Sinha, N., additional, Orlowska-Baranowska, E. H., additional, Placha, G., additional, Gora, J., additional, Baranowski, R., additional, Abramczuk, E., additional, Hryniewiecki, T., additional, Gaciong, Z., additional, Verschuren, J. J. W., additional, Wessels, J. A. M., additional, Trompet, S., additional, Stott, D. J., additional, Sattar, N., additional, Buckley, B., additional, Guchelaar, H. J., additional, Jukema, J. W., additional, Gharanei, M., additional, Hussain, A., additional, Mee, C. J., additional, Maddock, H. L., additional, Wijnen, W. J., additional, Van Den Oever, S., additional, Van Der Made, I., additional, Hiller, M., additional, Tijsen, A. J., additional, Pinto, Y. M., additional, Creemers, E. E., additional, Nikulina, S. U. Y., additional, Chernova, A., additional, Petry, A., additional, Rzymski, T., additional, Kracun, D., additional, Riess, F., additional, Pike, L., additional, Harris, A. L., additional, Gorlach, A., additional, Katare, R., additional, Oikawa, A., additional, Riu, F., additional, Beltrami, A. P., additional, Cesseli, D., additional, Emanueli, C., additional, Madeddu, P., additional, Zaglia, T., additional, Milan, G., additional, Franzoso, M., additional, Pesce, P., additional, Sarais, C., additional, Sandri, M., additional, Mongillo, M., additional, Butler, T. J., additional, Seymour, A.-M. L., additional, Ashford, D., additional, Jaffre, F., additional, Bussen, M., additional, Flohrschutz, I., additional, Martin, G. R., additional, Engelhardt, S., additional, Kararigas, G., additional, Nguyen, B. T., additional, Jarry, H., additional, Regitz-Zagrosek, V., additional, Van Bilsen, M., additional, Daniels, A., additional, Munts, C., additional, Janssen, B. J. A., additional, Van Der Vusse, G. J., additional, Van Nieuwenhoven, F. A., additional, Montalvo, C., additional, Villar, A. V., additional, Merino, D., additional, Garcia, R., additional, Llano, M., additional, Ares, M., additional, Hurle, M. A., additional, Nistal, J. F., additional, Dembinska-Kiec, A., additional, Beata Kiec-Wilk, B. K. W., additional, Anna Polus, A. P., additional, Urszula Czech, U. C., additional, Tatiana Konovaleva, T. K., additional, Gerd Schmitz, G. S., additional, Bertrand, L., additional, Balteau, M., additional, Timmermans, A., additional, Viollet, B., additional, Sakamoto, K., additional, Feron, O., additional, Horman, S., additional, Vanoverschelde, J. L., additional, Beauloye, C., additional, De Meester, C., additional, Martinez, E., additional, Martin, R., additional, Miana, M., additional, Jurado, R., additional, Gomez-Hurtado, N., additional, Bartolome, M. V., additional, San Roman, J. A., additional, Lahera, V., additional, Nieto, M. L., additional, Cachofeiro, V., additional, Rochais, F., additional, Sturny, R., additional, Mesbah, K., additional, Miquerol, L., additional, Kelly, R. G., additional, Messaoudi, S., additional, Gravez, B., additional, Tarjus, A., additional, Pelloux, V., additional, Samuel, J. L., additional, Delcayre, C., additional, Launay, J. M., additional, Clement, K., additional, Farman, N., additional, Jaisser, F., additional, Hadyanto, L., additional, Castellani, C., additional, Vescovo, G., additional, Ravara, B., additional, Tavano, R., additional, Pozzobon, M., additional, De Coppi, P., additional, Papini, E., additional, Vettor, R., additional, Thiene, G., additional, Angelini, A., additional, Meloni, M., additional, Caporali, A., additional, Cesselli, D., additional, Fortunato, O., additional, Avolio, E., additional, Schindler, R., additional, Simrick, S., additional, Brand, T., additional, Smart, N. S., additional, Herman, A., additional, Roura Ferrer, S., additional, Rodriguez Bago, J., additional, Soler-Botija, C., additional, Pujal, J. M., additional, Galvez-Monton, C., additional, Prat-Vidal, C., additional, Llucia-Valldeperas, A., additional, Blanco, J., additional, Bayes-Genis, A., additional, Foldes, G., additional, Maxime, M., additional, Ali, N. N., additional, Schneider, M. D., additional, Harding, S. E., additional, Reni, C., additional, Mangialardi, G., additional, De Pauw, A., additional, Sekkali, B., additional, Friart, A., additional, Ding, H., additional, Graffeuil, A., additional, Catalucci, D., additional, Balligand, J. L., additional, Azibani, F., additional, Tournoux, F., additional, Schlossarek, S., additional, Polidano, E., additional, Fazal, L., additional, Merval, R., additional, Carrier, L., additional, Chatziantoniou, C., additional, Buyandelger, B., additional, Linke, W., additional, Zou, P., additional, Kostin, S., additional, Ku, C., additional, Felkin, L., additional, Birks, E., additional, Barton, P., additional, Sattler, M., additional, Knoell, R., additional, Schroder, K., additional, Benkhoff, S., additional, Shimokawa, H., additional, Grisk, O., additional, Brandes, R. P., additional, Parepa, I. R., additional, Mazilu, L., additional, Suceveanu, A. I., additional, Suceveanu, A., additional, Rusali, L., additional, Cojocaru, L., additional, Matei, L., additional, Toringhibel, M., additional, Craiu, E., additional, Pires, A. L., additional, Pinho, M., additional, Pinho, S., additional, Sena, C., additional, Seica, R., additional, Leite-Moreira, A., additional, Dabroi, F., additional, Schiaffino, S., additional, Kiseleva, E., additional, Krukov, N., additional, Nikitin, O., additional, Ardatova, L., additional, Mourouzis, I., additional, Pantos, C., additional, Kokkinos, A. D., additional, Cokkinos, D. V., additional, Scoditti, E., additional, Massaro, M., additional, Carluccio, M. A., additional, Pellegrino, M., additional, Calabriso, N., additional, Gastaldelli, A., additional, Storelli, C., additional, De Caterina, R., additional, Lindner, D., additional, Zietsch, C., additional, Schultheiss, H.-P., additional, Tschope, C., additional, Westermann, D., additional, Everaert, B. R., additional, Nijenhuis, V. J., additional, Reith, F. C. M., additional, Hoymans, V. Y., additional, Timmermans, J. P., additional, Vrints, C. J., additional, Simova, I., additional, Mateev, H., additional, Katova, T., additional, Haralanov, L., additional, Dimitrov, N., additional, Mironov, N., additional, Golitsyn, S. P., additional, Sokolov, S. F., additional, Yuricheva, Y. U. A., additional, Maikov, E. B., additional, Shlevkov, N. B., additional, Rosenstraukh, L. V., additional, Chazov, E. I., additional, Radosinska, J., additional, Knezl, V., additional, Benova, T., additional, Slezak, J., additional, Urban, L., additional, Tribulova, N., additional, Virag, L., additional, Kristof, A., additional, Kohajda, Z. S., additional, Szel, T., additional, Husti, Z., additional, Baczko, I., additional, Jost, N., additional, Varro, A., additional, Sarusi, A., additional, Farkas, A. S., additional, Orosz, S. Z., additional, Forster, T., additional, Farkas, A., additional, Zakhrabova-Zwiauer, O. M., additional, Hardziyenka, M., additional, Nieuwland, R., additional, Tan, H. L., additional, Raaijmakers, A. J. A., additional, Bourgonje, V. J. A., additional, Kok, G. J. M., additional, Van Veen, A. A. B., additional, Anderson, M. E., additional, Vos, M. A., additional, Bierhuizen, M. F. A., additional, Benes, J., additional, Sebestova, B., additional, Ghouri, I. A., additional, Kemi, O. J., additional, Kelly, A., additional, Burton, F. L., additional, Smith, G. L., additional, Ozdemir, S., additional, Acsai, K., additional, Doisne, N., additional, Van Der Nagel, R., additional, Beekman, H. D. M., additional, Van Veen, T. A. B., additional, Sipido, K. R., additional, Antoons, G., additional, Harmer, S. C., additional, Mohal, J. S., additional, Kemp, D., additional, Tinker, A., additional, Beech, D., additional, Burley, D. S., additional, Cox, C. D., additional, Wann, K. T., additional, Baxter, G. F., additional, Wilders, R., additional, Verkerk, A., additional, Fragkiadaki, P., additional, Germanakis, G., additional, Tsarouchas, K., additional, Tsitsimpikou, C., additional, Tsardi, M., additional, George, D., additional, Tsatsakis, A., additional, Rodrigues, P., additional, Barros, C., additional, Najmi, A. K., additional, Khan, V., additional, Akhtar, M., additional, Pillai, K. K., additional, Mujeeb, M., additional, Aqil, M., additional, Bayliss, C. R., additional, Messer, A. E., additional, Leung, M.-C., additional, Ward, D., additional, Van Der Velden, J., additional, Poggesi, C., additional, Redwood, C. S., additional, Marston, S., additional, Vite, A., additional, Gandjbakhch, E., additional, Gary, F., additional, Fressart, V., additional, Leprince, P., additional, Fontaine, G., additional, Komajda, M., additional, Charron, P., additional, Villard, E., additional, Falcao-Pires, I., additional, Gavina, C., additional, Hamdani, N., additional, Stienen, G. J. M., additional, Niessens, H. W. M., additional, Leite-Moreira, A. F., additional, Paulus, W. J., additional, Memo, M., additional, Marston, S. B., additional, Vafiadaki, E., additional, Qian, J., additional, Arvanitis, D. A., additional, Sanoudou, D., additional, Kranias, E. G., additional, Elmstedt, N., additional, Lind, B., additional, Ferm-Widlund, K., additional, Westgren, M., additional, Brodin, L.-A., additional, Mansfield, C., additional, West, T., additional, Ferenczi, M., additional, Wijnker, P. J. M., additional, Foster, D. B., additional, Coulter, A., additional, Frazier, A., additional, Murphy, A. M., additional, Shah, M., additional, Sikkel, M. B., additional, Desplantez, T., additional, Collins, T. P., additional, O' Gara, P., additional, Lyon, A. R., additional, Macleod, K. T., additional, Ottesen, A. H., additional, Louch, W. E., additional, Carlson, C., additional, Landsverk, O. J. B., additional, Stridsberg, M., additional, Sjaastad, I., additional, Oie, E., additional, Omland, T., additional, Christensen, G., additional, Rosjo, H., additional, Cartledge, J., additional, Clark, L. A., additional, Ibrahim, M., additional, Siedlecka, U., additional, Navaratnarajah, M., additional, Yacoub, M. H., additional, Camelliti, P., additional, Terracciano, C. M., additional, Chester, A., additional, Gonzalez-Tendero, A., additional, Torre, I., additional, Garcia-Garcia, F., additional, Dopazo, J., additional, Gratacos, E., additional, Taylor, D., additional, Bhandari, S., additional, Seymour, A.-M., additional, Fliegner, D., additional, Jost, J., additional, Bugger, H., additional, Ventura-Clapier, R., additional, Carpi, A., additional, Campesan, M., additional, Canton, M., additional, Menabo, R., additional, Pelicci, P. G., additional, Giorgio, M., additional, Di Lisa, F., additional, Hancock, M., additional, Venturini, A., additional, Al-Shanti, N., additional, Stewart, C., additional, Ascione, R., additional, Angelini, G., additional, Suleiman, M.-S., additional, Kravchuk, E., additional, Grineva, E., additional, Galagudza, M., additional, Kostareva, A., additional, Bairamov, A., additional, Krychtiuk, K. A., additional, Watzke, L., additional, Kaun, C., additional, Demyanets, S., additional, Pisoni, J., additional, Kastl, S. P., additional, Huber, K., additional, Maurer, G., additional, Wojta, J., additional, Speidl, W. S., additional, Varga, Z. V., additional, Farago, N., additional, Zvara, A., additional, Kocsis, G. F., additional, Pipicz, M., additional, Csonka, C., additional, Csont, T., additional, Puskas, G. L., additional, Ferdinandy, P., additional, Klevstigova, M., additional, Silhavy, J., additional, Manakov, D., additional, Papousek, F., additional, Novotny, J., additional, Pravenec, M., additional, Kolar, F., additional, Novakova, O., additional, Novak, F., additional, Neckar, J., additional, Barallobre-Barreiro, J., additional, Didangelos, A., additional, Yin, X., additional, Fernandez-Caggiano, M., additional, Drozdov, I., additional, Willeit, P., additional, Domenech, N., additional, Mayr, M., additional, Lemoine, S., additional, Allouche, S., additional, Coulbault, L., additional, Galera, P., additional, Gerard, J. L., additional, Hanouz, J. L., additional, Suveren, E., additional, Whiteman, M., additional, Studneva, I. M., additional, Pisarenko, O., additional, Shulzhenko, V., additional, Serebryakova, L., additional, Tskitishvili, O., additional, Timoshin, A., additional, Fauconnier, J., additional, Meli, A. C., additional, Thireau, J., additional, Roberge, S., additional, Lompre, A. M., additional, Jacotot, E., additional, Marks, A. M., additional, Lacampagne, A., additional, Dietel, B., additional, Altendorf, R., additional, Daniel, W. G., additional, Kollmar, R., additional, Garlichs, C. D., additional, Parente, V., additional, Balasso, S., additional, Pompilio, G., additional, Colombo, G., additional, Milano, G., additional, Squadroni, L., additional, Cotelli, F., additional, Pozzoli, O., additional, Capogrossi, M. C., additional, Ajiro, Y., additional, Saegusa, N., additional, Iwade, K., additional, Giles, W. R., additional, Stafforini, D. M., additional, Spitzer, K. W., additional, Sirohi, R., additional, Candilio, L., additional, Babu, G., additional, Roberts, N., additional, Lawrence, D., additional, Sheikh, A., additional, Kolvekar, S., additional, Yap, J., additional, Hausenloy, D. J., additional, Yellon, D. M., additional, Aslam, M., additional, Rohrbach, S., additional, Schlueter, K.-D., additional, Piper, H. M., additional, Noll, T., additional, Guenduez, D., additional, Malinova, L., additional, Ryabukho, V. P., additional, Lyakin, D. V., additional, Denisova, T. P., additional, Montoro-Garcia, S., additional, Shantsila, E., additional, Lip, G. Y. H., additional, Kalaska, B., additional, Sokolowska, E., additional, Kaminski, K., additional, Szczubialka, K., additional, Kramkowski, K., additional, Mogielnicki, A., additional, Nowakowska, M., additional, Buczko, W., additional, Stancheva, N., additional, Mekenyan, E., additional, Gospodinov, K., additional, Tisheva, S., additional, Darago, A., additional, Rutkai, I., additional, Kalasz, J., additional, Czikora, A., additional, Orosz, P., additional, Bjornson, H. D., additional, Edes, I., additional, Papp, Z., additional, Toth, A., additional, Riches, K., additional, Warburton, P., additional, O'regan, D. J., additional, Ball, S. 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P., additional, Roncon-Albuquerque, R., additional, Oyeyipo, I. P., additional, Olatunji, L. A., additional, Usman, T. O., additional, Olatunji, V. A., additional, Bacova, B., additional, Viczenczova, C., additional, Dosenko, V., additional, Goncalvesova, E., additional, Vanrooyen, J., additional, Maulik, S. K., additional, Seth, S., additional, Dinda, A. K., additional, Jaiswal, A., additional, Mearini, G., additional, Khajetoorians, D., additional, Kraemer, E., additional, Gedicke-Hornung, C., additional, Precigout, G., additional, Eschenhagen, T., additional, Voit, T., additional, Garcia, L., additional, Lorain, S., additional, Mendes-Ferreira, P., additional, Maia-Rocha, C., additional, Adao, R., additional, Cerqueira, R. J., additional, Mendes, M. J., additional, Castro-Chaves, P., additional, De Keulenaer, G. W., additional, Bras-Silva, C., additional, Ruiter, G., additional, Wong, Y. 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J., additional, Llacer, A., additional, Galasso, G., additional, Ferrara, N., additional, Akhmedov, A., additional, Klingenberg, R., additional, Brokopp, C., additional, Hof, D., additional, Zoller, S., additional, Corti, R., additional, Gay, S., additional, Von Eckardstein, A., additional, Hoerstrup, S. P., additional, Luescher, T. F., additional, Heijman, J., additional, Zaza, A., additional, Johnson, D. M., additional, Rudy, Y., additional, Peeters, R. L. M., additional, Volders, P. G. A., additional, Westra, R. L., additional, Fujita, S., additional, Okamoto, R., additional, Taniguchi, M., additional, Konishi, K., additional, Goto, I., additional, Sugimoto, K., additional, Nakamura, M., additional, Shiraki, K., additional, Buechler, C., additional, and Ito, M., additional

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2012
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22. Poster session 2

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Perez-Pomares, J. M., primary, Ruiz-Villalba, A., additional, Ziogas, A., additional, Segovia, J. C., additional, Ehrbar, M., additional, Munoz-Chapuli, R., additional, De La Rosa, A., additional, Dominguez, J. N., additional, Hove-Madsen, L., additional, Sankova, B., additional, Sedmera, D., additional, Franco, D., additional, Aranega Jimenez, A., additional, Babaeva, G., additional, Chizh, N., additional, Galchenko, S., additional, Sandomirsky, B., additional, Schwarzl, M., additional, Seiler, S., additional, Steendijk, P., additional, Huber, S., additional, Maechler, H., additional, Truschnig-Wilders, M., additional, Pieske, B., additional, Post, H., additional, Simrick, S., additional, Kreutzer, R., additional, Rao, C., additional, Terracciano, C. M., additional, Kirchhof, P., additional, Fabritz, L., additional, Brand, T., additional, Theveniau-Ruissy, M., additional, Parisot, P., additional, Francou, A., additional, Saint-Michel, E., additional, Mesbah, K., additional, Kelly, R. G., additional, Wu, H.-T., additional, Sie, S.-S., additional, Chen, C.-Y., additional, Kuan, T.-C., additional, Lin, C. S., additional, Ismailoglu, Z., additional, Guven, M., additional, Yakici, A., additional, Ata, Y., additional, Ozcan, S., additional, Yildirim, E., additional, Ongen, Z., additional, Miroshnikova, V., additional, Demina, E., additional, Rodygina, T., additional, Kurjanov, P., additional, Denisenko, A., additional, Schwarzman, A., additional, Rubanenko, A., additional, Shchukin, Y., additional, Germanov, A., additional, Goldbergova, M., additional, Parenica, J., additional, Lipkova, J., additional, Pavek, N., additional, Kala, P., additional, Poloczek, M., additional, Vasku, A., additional, Parenicova, I., additional, Spinar, J., additional, Gambacciani, C., additional, Chiavacci, E., additional, Evangelista, M., additional, Vesentini, N., additional, Kusmic, C., additional, Pitto, L., additional, Chernova, A., additional, Nikulina, S. U. Y., additional, Arvanitis, D. A., additional, Mourouzis, I., additional, Pantos, C., additional, Kranias, E. G., additional, Cokkinos, D. V., additional, Sanoudou, D., additional, Vladimirskaya, T. E., additional, Shved, I. A., additional, Kryvorot, S. G., additional, Schirmer, I. M., additional, Appukuttan, A., additional, Pott, L., additional, Jaquet, K., additional, Ladilov, Y., additional, Archer, C. R., additional, Bootman, M. D., additional, Roderick, H. L., additional, Fusco, A., additional, Sorriento, D., additional, Santulli, G., additional, Trimarco, B., additional, Iaccarino, G., additional, Hagenmueller, M., additional, Riffel, J., additional, Bernhold, E., additional, Katus, H. A., additional, Hardt, S. 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C., additional, Schmeisser, A., additional, Strasser, R. H., additional, Micova, P., additional, Balkova, P., additional, Hlavackova, M., additional, Zurmanova, J., additional, Kasparova, D., additional, Kolar, F., additional, Neckar, J., additional, Novak, F., additional, Novakova, O., additional, Pollard, S., additional, Babba, M., additional, Hussain, A., additional, James, R., additional, Maddock, H., additional, Alshehri, A. S., additional, Baxter, G. F., additional, Dietel, B., additional, Altendorf, R., additional, Daniel, W. G., additional, Kollmar, R., additional, Garlichs, C. D., additional, Sirohi, R., additional, Roberts, N., additional, Lawrence, D., additional, Sheikh, A., additional, Kolvekar, S., additional, Yap, J., additional, Arend, M., additional, Walkinshaw, G., additional, Hausenloy, D. J., additional, Yellon, D. M., additional, Posa, A., additional, Szabo, R., additional, Szalai, Z., additional, Szablics, P., additional, Berko, M. A., additional, Orban, K., additional, Murlasits, Z. S., additional, Balogh, L., additional, Varga, C., additional, Ku, H. C., additional, Su, M. J., additional, Chreih, R.-M., additional, Ginghina, C., additional, Deleanu, D., additional, Ferreira, A. L. B. J., additional, Belal, A., additional, Ali, M. A., additional, Fan, X., additional, Holt, A., additional, Campbell, R., additional, Schulz, R., additional, Bonanad, C., additional, Bodi, V., additional, Sanchis, J., additional, Morales, J. M., additional, Marrachelli, V., additional, Nunez, J., additional, Forteza, M. J., additional, Chaustre, F., additional, Gomez, C., additional, Chorro, F. J., additional, Csont, T., additional, Fekete, V., additional, Murlasits, Z., additional, Aypar, E., additional, Bencsik, P., additional, Sarkozy, M., additional, Varga, Z. V., additional, Ferdinandy, P., additional, Duerr, G. 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P., additional, Gullestad, L., additional, Carpi, A., additional, Di Lisa, F., additional, Giorgio, M., additional, Vaage, J., additional, Valen, G., additional, Vafiadaki, E., additional, Papalouka, V., additional, Terzis, G., additional, Spengos, K., additional, Manta, P., additional, Gales, C., additional, Genet, G., additional, Dague, E., additional, Cazorla, O., additional, Payre, B., additional, Mias, C., additional, Ouille, A., additional, Lacampagne, A., additional, Pathak, A., additional, Senard, J. 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R., additional, Devaux, Y., additional, Torre, I., additional, Psilodimitrakopoulos, S., additional, Iruretagoiena, I., additional, Gonzalez-Tendero, A., additional, Artigas, D., additional, Loza-Alvarez, P., additional, Gratacos, E., additional, Amat-Roldan, I., additional, Murray, L., additional, Carberry, D. M., additional, Dunton, P., additional, Miles, M. J., additional, Suleiman, M.-S., additional, Kanesalingam, K., additional, Taylor, R., additional, Mc Collum, C. N., additional, Parniczky, A., additional, Solymar, M., additional, Porpaczy, A., additional, Miseta, A., additional, Lenkey, Z. S., additional, Szabados, S., additional, Cziraki, A., additional, Garai, J., additional, Myloslavska, I., additional, Menazza, S. M., additional, Canton, M. C., additional, Di Lisa, F. D. L., additional, Oliveira, S. H. V., additional, Morais, C. A. S., additional, Miranda, M. R., additional, Oliveira, T. T., additional, Lamego, M. R. A., additional, Lima, L. M., additional, Goncharova, N. S., additional, Naymushin, A. V., additional, Kazimli, A. V., additional, Moiseeva, O. M., additional, Carvalho, M. G., additional, Sabino, A. P., additional, Mota, A. P. L., additional, Sousa, M. O., additional, Niessner, A., additional, Richter, B., additional, Hohensinner, P. J., additional, Rychli, K., additional, Zorn, G., additional, Berger, R., additional, Moertl, D., additional, Pacher, R., additional, Wojta, J., additional, Huelsmann, M., additional, Kukharchik, G., additional, Nesterova, N., additional, Pavlova, A., additional, Gaykovaya, L., additional, Krapivka, N., additional, Konstantinova, I., additional, Sichinava, L., additional, Prapa, S., additional, Mccarthy, K. P., additional, Kilner, P. J., additional, Xu, X. Y., additional, Johnson, M. R., additional, Ho, S. Y., additional, Gatzoulis, M. A., additional, Stoupel, E. G., additional, Garcia, R., additional, Merino, D., additional, Montalvo, C., additional, Hurle, M. A., additional, Nistal, J. F., additional, Villar, A. V., additional, Perez-Moreno, A., additional, Gilabert, R., additional, and Ros, E., additional

Published
2012
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24. Increased Gene Expression of the Cardiac Endothelin System in Obese Mice.

Author

Catar, R. A., Muller, G., Brandt, A., Langbein, H., Brunssen, C., Goettsch, C., Frenzel, A., Hofmann, A., Goettsch, W., Steinbronn, N., Strasser, R. H., Schubert, U., Ludwig, B., Bornstein, S. R., and Morawietz, H.

Subjects
GENE expression, ENDOTHELINS, OBESITY, LOW density lipoproteins, CHOLESTEROL in the body, HIGH density lipoproteins, CARDIAC hypertrophy
Abstract

Obesity is a well-known risk factor of atherosclerosis and heart failure. In the human heart, a local endothelin system containing prepro-endothelin- 1, endothelin-converting enzyme-1, and endothelin receptors A and B has been described. The endothelin system is activated in heart failure; however, the impact of obesity on the cardiac endothelin system is unknown. In this study, 18-week-old male C57BL/6 mice fed either a control diet or a high-fat diet for 10 weeks were analyzed. High-fat diet significantly increased the body weight of the animals and augmented low-density lipoprotein, high-density lipoprotein, and cholesterol plasma levels, compared to control. The animal groups showed no significant differences in left ventricular size or function (heart rate, ejection fraction, fractional shortening, left ventricular posterior wall thickness, cardiac output) after control or high-fat diet. We did not observe signs of cardiac hypertrophy or changes in markers of cardiac fibrosis in these heart samples. The cardiac expression of prepro-endothelin-1 mRNA, endothelin-converting enzyme-1 mRNA, and protein and endothelin receptors A and B mRNA was increased in 18-week-old obese C57BL/6 mice compared to animals with normal weight (p < 0.05 vs. control). Furthermore, endothelin-1 plasma levels showed an increasing trend. In conclusion, an increased expression of genes of the endothelin system was observed in the hearts of 18-week-old mice after high-fat diet, possibly contributing to later cardiovascular complications of obesity. [ABSTRACT FROM AUTHOR]

Published
2015
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25. NADPH Oxidase 4: Crucial for Endothelial Function under Hypoxia-Complementing Prostacyclin.

Author

Brendel H, Mittag J, Hofmann A, Hempel H, Giebe S, Diaba-Nuhoho P, Wolk S, Reeps C, Morawietz H, and Brunssen C

Abstract

Aim : The primary endothelial NADPH oxidase isoform 4 (NOX4) is notably induced during hypoxia, with emerging evidence suggesting its vasoprotective role through H 2 O 2 production. Therefore, we aimed to elucidate NOX4's significance in endothelial function under hypoxia. Methods : Human vessels, in addition to murine vessels from Nox4 -/- mice, were explored. On a functional level, Mulvany myograph experiments were performed. To obtain mechanistical insights, human endothelial cells were cultured under hypoxia with inhibitors of hypoxia-inducible factors. Additionally, endothelial cells were cultured under combined hypoxia and laminar shear stress conditions. Results : In human occluded vessels, NOX4 expression strongly correlated with prostaglandin I2 synthase ( PTGIS ). Hypoxia significantly elevated NOX4 and PTGIS expression and activity in human endothelial cells. Inhibition of prolyl hydroxylase domain (PHD) enzymes, which stabilize hypoxia-inducible factors (HIFs), increased NOX4 and PTGIS expression even under normoxic conditions. NOX4 mRNA expression was reduced by HIF1a inhibition, while PTGIS mRNA expression was only affected by the inhibition of HIF2a under hypoxia. Endothelial function assessments revealed hypoxia-induced endothelial dysfunction in mesenteric arteries from wild-type mice. Mesenteric arteries from Nox4 -/- mice exhibited an altered endothelial function under hypoxia, most prominent in the presence of cyclooxygenase inhibitor diclofenac to exclude the impact of prostacyclin. Restored protective laminar shear stress, as it might occur after thrombolysis, angioplasty, or stenting, attenuated the hypoxic response in endothelial cells, reducing HIF1a expression and its target NOX4 while enhancing eNOS expression. Conclusions : Hypoxia strongly induces NOX4 and PTGIS, with a close correlation between both factors in occluded, hypoxic human vessels. This relationship ensured endothelium-dependent vasodilation under hypoxic conditions. Protective laminar blood flow restores eNOS expression and mitigates the hypoxic response on NOX4 and PTGIS., Competing Interests: The authors declare no conflicts of interest.

Published
2024
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26. The Vascular Function of Resistance Arteries Depends on NADPH Oxidase 4 and Is Exacerbated by Perivascular Adipose Tissue.

Author

Diaba-Nuhoho P, Mittag J, Brunssen C, Morawietz H, and Brendel H

Abstract

The NADPH oxidase NOX4 that releases H 2 O 2 can mediate vasoprotective mechanisms under pathophysiological conditions in conductive arteries. However, the role of NOX4 in resistance arteries and in perivascular adipose tissue is not well understood. We hypothesized that NOX4 is of functional importance in resistance arteries and perivascular adipose tissue under dyslipidemia conditions. We detected elevated NOX4 expression in murine and human vessels under dyslipidemia. Diminishing Nox4 under these conditions led to endothelial dysfunction in resistance arteries. The mesenteric arteries of Nox4 -/- / Ldlr -/- mice revealed decreased eNos mRNA expression. Inhibition of eNOS in those vessels did not affect vascular function, while in Ldlr -/- mice endothelial function was significantly altered. Anticontractile properties of perivascular adipose tissue at resistance arteries were diminished in Nox4 -/- / Ldlr -/- compared with Ldlr -/- mice. In addition, the presence of perivascular adipose tissue further worsened endothelial dysfunction in mesenteric arteries under dyslipidemia conditions. Perivascular adipose tissue from mesenteric arteries revealed a higher expression of markers of white adipocytes compared to markers of beige/brown adipocytes. Among those white adipocyte markers, leptin was significantly less expressed in perivascular adipose tissue from Nox4 -/- / Ldlr -/- mice compared with Ldlr -/- mice. Furthermore, in human perivascular adipose tissue with a profound pattern of white adipocyte marker genes, we detected a correlation of NOX4 and LEP expression. In addition, incubating arterial vessels with leptin induced nitrite release, indicating increased eNOS activity. In humans, a higher expression of leptin in perivascular adipose tissue correlated with eNOS expression in the corresponding left internal mammary artery. In conclusion, vascular function of resistance arteries was dependent on Nox4 -derived H 2 O 2 , especially under dyslipidemia conditions. Perivascular adipose tissue of the mesenteric arteries with white adipose tissue characteristics further aggravated endothelial function through reduced leptin-eNOS signaling.

Published
2024
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27. The Role of NOX2-Derived Reactive Oxygen Species in the Induction of Endothelin-Converting Enzyme-1 by Angiotensin II.

Author

Adu-Gyamfi M, Goettsch C, Kamhieh-Milz J, Chen L, Pfefferkorn AM, Hofmann A, Brunssen C, Müller G, Walther T, Ashraf MI, Morawietz H, Witowski J, and Catar R

Abstract

Endothelin-1 is a key regulator of vascular tone and blood pressure in health and disease. We have recently found that ET-1 production in human microvascular endothelial cells (HMECs) can be promoted by angiotensin II (Ang II) through a novel mechanism involving octamer-binding transcription factor-1 (Oct-1), NADPH oxidase-2 (NOX2), and superoxide anions. As the formation of bioactive ET-1 also depends on endothelin-converting enzyme-1 (ECE-1), we investigated the transcriptional regulation of the ECE1 gene. We found that exposure of HMECs to Ang II resulted in a concentration- and time-dependent increase in ECE1 mRNA expression. Pharmacological inhibition of ECE-1 reduced Ang II-stimulated ET-1 release to baseline values. The effect of Ang II on ECE1 mRNA expression was associated with Oct-1 binding to the ECE1 promoter, resulting in its increased activity. Consequently, the Ang II-stimulated increase in ECE1 mRNA expression could be prevented by siRNA-mediated Oct-1 inhibition. It could also be abolished by silencing the NOX2 gene and neutralizing superoxide anions with superoxide dismutase. In mice fed a high-fat diet, cardiac expression of Ece1 mRNA increased in wild-type mice but not in Nox2 -deficient animals. It can be concluded that Ang II engages Oct-1, NOX2, and superoxide anions to stimulate ECE1 expression in the endothelium.

Published
2024
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28. Modulation of the hippo-YAP pathway by cyclic stretch in rat type 2 alveolar epithelial cells-a proof-of-concept study.

Author

Ran X, Müller S, Brunssen C, Huhle R, Scharffenberg M, Schnabel C, Koch T, Gama de Abreu M, Morawietz H, Ferreira JMC, and Wittenstein J

Abstract

Background: Mechanical ventilation (MV) is a life supporting therapy but may also cause lung damage. This phenomenon is known as ventilator-induced lung injury (VILI). A potential pathomechanisms of ventilator-induced lung injury may be the stretch-induced production and release of cytokines and pro-inflammatory molecules from the alveolar epithelium. Yes-associated protein (YAP) might be regulated by mechanical forces and involved in the inflammation cascade. However, its role in stretch-induced damage of alveolar cells remains poorly understood. In this study, we explored the role of YAP in the response of alveolar epithelial type II cells (AEC II) to elevated cyclic stretch in vitro . We hypothesize that Yes-associated protein activates its downstream targets and regulates the interleukin-6 (IL-6) expression in response to 30% cyclic stretch in AEC II. Methods: The rat lung L2 cell line was exposed to 30% cyclic equibiaxial stretch for 1 or 4 h. Non-stretched conditions served as controls. The cytoskeleton remodeling and cell junction integrity were evaluated by F-actin and Pan-cadherin immunofluorescence, respectively. The gene expression and protein levels of IL-6, Yes-associated protein, Cysteine-rich angiogenic inducer 61 (Cyr61/CCN1), and connective tissue growth factor (CTGF/CCN2) were studied by real-time polymerase chain reaction (RT-qPCR) and Western blot, respectively. Verteporfin (VP) was used to inhibit Yes-associated protein activation. The effects of 30% cyclic stretch were assessed by two-way ANOVA. Statistical significance as accepted at p < 0.05. Results: Cyclic stretch of 30% induced YAP nuclear accumulation, activated the transcription of Yes-associated protein downstream targets Cyr61/CCN1 and CTGF/CCN2 and elevated IL-6 expression in AEC II after 1 hour, compared to static control. VP (2 µM) inhibited Yes-associated protein activation in response to 30% cyclic stretch and reduced IL-6 protein levels. Conclusion: In rat lung L2 AEC II, 30% cyclic stretch activated YAP, and its downstream targets Cyr61/CCN1 and CTGF/CCN2 and proinflammatory IL-6 expression. Target activation was blocked by a Yes-associated protein inhibitor. This novel YAP-dependent pathway could be involved in stretch-induced damage of alveolar cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ran, Müller, Brunssen, Huhle, Scharffenberg, Schnabel, Koch, Gama de Abreu, Morawietz, Ferreira and Wittenstein.)

Published
2023
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29. PLAC8-Mediated Activation of NOX4 Signalling Restores Angiogenic Function of Endothelial Colony-Forming Cells in Experimental Hypoxia.

Author

Pun SH, O'Neill KM, Edgar KS, Gill EK, Moez A, Naderi-Meshkin H, Malla SB, Hookham MB, Alsaggaf M, Madishetti VV, Botezatu B, King W, Brunssen C, Morawietz H, Dunne PD, Brazil DP, Medina RJ, Watson CJ, and Grieve DJ

Subjects
Humans, Endothelial Cells metabolism, Fetal Blood cytology, Fetal Blood metabolism, Hydrogen Peroxide metabolism, NADPH Oxidase 4 metabolism, NADPH Oxidase 4 genetics, NF-E2-Related Factor 2 metabolism, Reactive Oxygen Species metabolism, Cell Hypoxia, Neovascularization, Physiologic genetics, Signal Transduction
Abstract

Ischaemic cardiovascular disease is associated with tissue hypoxia as a significant determinant of angiogenic dysfunction and adverse remodelling. While cord blood-derived endothelial colony-forming cells (CB-ECFCs) hold clear therapeutic potential due to their enhanced angiogenic and proliferative capacity, their impaired functionality within the disease microenvironment represents a major barrier to clinical translation. The aim of this study was to define the specific contribution of NOX4 NADPH oxidase, which we previously reported as a key CB-ECFC regulator, to hypoxia-induced dysfunction and its potential as a therapeutic target. CB-ECFCs exposed to experimental hypoxia demonstrated downregulation of NOX4-mediated reactive oxygen species (ROS) signalling linked with a reduced tube formation, which was partially restored by NOX4 plasmid overexpression. siRNA knockdown of placenta-specific 8 (PLAC8), identified by microarray analysis as an upstream regulator of NOX4 in hypoxic versus normoxic CB-ECFCs, enhanced tube formation, NOX4 expression and hydrogen peroxide generation, and induced several key transcription factors associated with downstream Nrf2 signalling. Taken together, these findings indicated that activation of the PLAC8-NOX4 signalling axis improved CB-ECFC angiogenic functions in experimental hypoxia, highlighting this pathway as a potential target for protecting therapeutic cells against the ischaemic cardiovascular disease microenvironment.

Published
2023
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30. Ang II Promotes ET-1 Production by Regulating NOX2 Activity Through Transcription Factor Oct-1.

Author

Kamhieh-Milz J, Chen L, Goettsch C, Pfefferkorn AM, Hofmann A, Brunssen C, Müller GM, Walther T, Ashraf MI, Moll G, Morawietz H, Witowski J, and Catar R

Subjects
Mice, Animals, Humans, Octamer Transcription Factor-1, NADPH Oxidases genetics, NADPH Oxidases metabolism, Angiotensin II pharmacology, Angiotensin II metabolism, Reactive Oxygen Species metabolism, Superoxides metabolism, Endothelial Cells metabolism
Abstract

Background: Increasing evidence suggests that superoxide ions produced by NOX (nicotinamide adenine dinucleotide phosphate oxidases) mediate vascular effects of Ang II (angiotensin II) evoked by atherogenic diets. Here, we analyzed the mechanism by which NOX2 contributes to Ang II-induced ET-1 (endothelin 1) production in human microvascular endothelial cells., Methods: The effects of high-fat diet were compared between WT (wild type) and Nox2 ( mouse NOX2 gene )-deficient mice. ET-1 production and NOX2 expression by human microvascular endothelial cells in vitro were analyzed by ELISA, reverse transcription quantitative polymerase chain reaction, electrophoretic mobility shift assay, promoter deletions, RNA interference, and pharmacological inhibition. Production of superoxide anions was visualized by fluorescent cell labeling., Results: Feeding mice high-fat diet for 10 weeks increased cardiac expression and plasma levels of Ang II and ET-1 in WT but not in Nox2 -deficient animals. Exposure of human microvascular endothelial cells to Ang II resulted in increased ET-1 production, which could be blocked by silencing NOX2 ( human NOX2 gene ). Ang II promoted NOX2 expression through induction of the Oct-1 (human/mouse octamer binding transcription factor 1 protein) and activation of the NOX2 promoter region containing Oct-1-binding sites. Stimulation of NOX2 expression by Ang II was associated with increased production of superoxide anions. Inhibition of Oct-1 by small interfering RNA reduced Ang II-induced NOX2 expression and superoxide anion production, and neutralization of superoxide by SOD (superoxide dismutase) abolished Ang II-stimulated ET1 ( human ET-1 gene ) promoter activity, ET1 mRNA expression, and ET-1 release., Conclusions: Ang II may promote ET-1 production in the endothelium in response to atherogenic diets through a mechanism that involves the transcription factor Oct-1 and the increased formation of superoxide anions by NOX2., Competing Interests: Disclosures None.

Published
2023
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31. Associations of Tissue and Soluble LOX-1 with Human Abdominal Aortic Aneurysm.

Author

Hofmann A, Khorzom Y, Klimova A, Wolk S, Busch A, Sabarstinski P, Müglich M, Egorov D, Kopaliani I, Poitz DM, Kapalla M, Hamann B, Frank F, Jänichen C, Brunssen C, Morawietz H, and Reeps C

Subjects
Humans, Biomarkers, Case-Control Studies, RNA, Messenger, Scavenger Receptors, Class E, Aortic Aneurysm, Abdominal genetics, Atherosclerosis, Diabetes Mellitus, Type 2, Peripheral Arterial Disease
Abstract

Background Indication for prophylactic surgical abdominal aortic aneurysm (AAA) repair depends on the maximal aortic diameter. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major receptor for uptake of oxidized low-density lipoprotein cholesterol and is implicated in atherosclerosis. A soluble form of LOX-1 (sLOX-1) has been discussed as a novel biomarker in coronary artery disease and stroke. Herein, we assessed the regulation of aortic LOX-1 as well as the diagnostic and risk stratification potential of sLOX-1 in patients with AAA. Methods and Results Serum sLOX-1 was assessed in a case-control study in AAA (n=104) and peripheral artery disease (n=104). sLOX-1 was not statistically different between AAA and peripheral artery disease but was higher in AAA (β=1.28, P =0.04) after adjusting for age, atherosclerosis, type 2 diabetes, prescription of statins, β-blockers, ACE inhibitors, and therapeutic anticoagulation. sLOX-1 was not associated with the aortic diameter, AAA volume, or the thickness of the intraluminal thrombus. Aortic LOX-1 mRNA expression tended to be higher in AAA when compared with disease, and expression was positively associated with cleaved caspase-3, smooth muscle actin, collagen, and macrophage content. Conclusions In AAA, sLOX-1 was differently affected by age, cardiometabolic diseases, and corresponding medical therapies. Comparison with nonatherosclerotic disease would be beneficial to further elucidate the diagnostic potential of sLOX-1, although it was not useful for risk stratification. Aneurysmal LOX-1 mRNA expression was increased and positively associated with smooth muscle cells and collagen content, suggesting that LOX-1 is eventually not deleterious in human AAA and could counteract AAA rupture.

Published
2023
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32. Regulation of endothelial function by cigarette smoke and next-generation tobacco and nicotine products.

Author

Klein J, Diaba-Nuhoho P, Giebe S, Brunssen C, and Morawietz H

Subjects
Nicotine adverse effects, Endothelium, Vascular, Cigarette Smoking, Atherosclerosis
Abstract

Cigarette smoking is the most important avoidable cardiovascular risk factor. It causes endothelial dysfunction and atherosclerosis and increases the risk of its severe clinical complications like coronary artery disease, myocardial infarction, stroke, and peripheral artery disease. Several next-generation tobacco and nicotine products have been developed to decrease some of the deleterious effects of regular tobacco smoking. This review article summarizes recent findings about the impact of cigarette smoking and next-generation tobacco and nicotine products on endothelial dysfunction. Both cigarette smoking and next-generation tobacco products lead to impaired endothelial function. Molecular mechanisms of endothelial dysfunction like oxidative stress, reduced nitric oxide availability, inflammation, increased monocyte adhesion, and cytotoxic effects of cigarette smoke and next-generation tobacco and nicotine products are highlighted. The potential impact of short- and long-term exposure to next-generation tobacco and nicotine products on the development of endothelial dysfunction and its clinical implications for cardiovascular diseases are discussed., (© 2023. The Author(s).)

Published
2023
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33. Comparative study of the effects of cigarette smoke versus next-generation tobacco and nicotine product extracts on inflammatory biomarkers of human monocytes.

Author

Giebe S, Brux M, Hofmann A, Lowe F, Breheny D, Morawietz H, and Brunssen C

Subjects
Humans, Nicotine pharmacology, Monocytes, Interleukin-8, Biomarkers, Cigarette Smoking adverse effects, Electronic Nicotine Delivery Systems
Abstract

Monocytes exhibiting a pro-inflammatory phenotype play a key role in adhesion and development of atherosclerotic plaques. As an alternative to smoking, next-generation tobacco and nicotine products (NGP) are now widely used. However, little is known about their pro-inflammatory effects on monocytes. We investigated cell viability, anti-oxidant and pro-inflammatory gene and protein expression in THP-1 monocytes after exposure to aqueous smoke extracts (AqE) of a heated tobacco product (HTP), an electronic cigarette (e-cig), a conventional cigarette (3R4F) and pure nicotine (nic). Treatment with 3R4F reduced cell viability in a dose-dependent manner, whereas exposure to alternative smoking products showed no difference to control. At the highest non-lethal dose of 3R4F (20%), the following notable mRNA expression changes were observed for 3R4F, HTP, and e-cig respectively, relative to control; HMOX1 (6-fold, < 2-fold, < 2-fold), NQO1 (3.5-fold, < 2-fold, < 2-fold), CCL2 (4-fold, 3.5-fold, 2.5-fold), IL1B (4-fold, 3-fold, < 2-fold), IL8 (5-fold, 2-fold, 2-fold), TNF (2-fold, 2-fold, < 2-fold) and ICAM1 was below the 2-fold threshold for all products. With respect to protein expression, IL1B (3-fold, < 2-fold, < 2-fold) and IL8 (3.5-fold, 2-fold, 2-fold) were elevated over the 2-fold threshold, whereas CCL2, TNF, and ICAM1 were below 2-fold expression for all products. At higher doses, greater inductions were observed with all extracts; however, NGP responses were typically lower than 3R4F. In conclusion, anti-oxidative and pro-inflammatory processes were activated by all products. NGPs overall showed lower responses relative to controls than THP-1 cells exposed to 3R4F AqE., (© 2023. The Author(s).)

Published
2023
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34. Aprotinin does not Impair Vascular Function in Patients Undergoing Coronary Artery Bypass Graft Surgery.

Author

Tolkmitt J, Brendel H, Zatschler B, Brose S, Brunssen C, Kopaliani I, Deussen A, Matschke K, and Morawietz H

Subjects
Humans, Rats, Animals, Endothelial Cells metabolism, Coronary Artery Bypass, Serine Proteinase Inhibitors pharmacology, Aprotinin pharmacology, Nitric Oxide Synthase Type III metabolism
Abstract

Bleeding is a major complication in coronary artery bypass graft surgery. Antifibrinolytic agents like serine protease inhibitor aprotinin can decrease postoperative bleeding and complications of cardiac surgery. However, the effects of aprotinin on vascular function are not completely elucidated. We compared the ex vivo vascular function of left internal mammary arteries from patients undergoing coronary artery bypass graft surgery with and without intraoperative application of aprotinin using a Mulvany Myograph. Human internal mammary arteries were treated with aprotinin ex vivo and tested for changes in vascular function. We analyzed the impact of aprotinin on vascular function in rat aortic rings. Finally, impact of aprotinin on expression and activity of endothelial nitric oxide synthase was tested in human endothelial cells. Intraoperative application of aprotinin did not impair ex vivo vascular function of internal mammary arteries of patients undergoing coronary artery bypass graft surgery. Endothelium-dependent and -independent relaxations were not different in patients with or without aprotinin after nitric oxide synthase blockade. A maximum vasorelaxation of 94.5%±11.4vs. 96.1%±5.5% indicated a similar vascular smooth muscle function in both patient groups (n=13 each). Long-term application of aprotinin under physiological condition preserved vascular function of the rat aorta. In vitro application of increasing concentrations of aprotinin on human endothelial cells resulted in a similar expression and activity of endothelial nitric oxide synthase. In conclusion, intraoperative and ex vivo application of aprotinin does not impair the endothelial function in human internal mammary arteries and experimental models., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Published
2023
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35. NOX4 mRNA correlates with plaque stability in patients with carotid artery stenosis.

Author

Hofmann A, Frank F, Wolk S, Busch A, Klimova A, Sabarstinski P, Gerlach M, Egorov D, Kopaliani I, Weinert S, Hamann B, Poitz DM, Brunssen C, Morawietz H, Schröder K, and Reeps C

Abstract

Carotid artery stenosis (CAS) develops from atherosclerotic lesions and plaques. Plaque rupture or stenosis may result in occlusion of the carotid artery. Accordingly, the asymptomatic disease becomes symptomatic, characterized by ischemic stroke or transient ischemic attacks, indicating an urgent need for better understanding of the underlying molecular mechanisms and eventually prevent symptomatic CAS. NOX4, a member of the NADPH oxidase family, has anti-atherosclerotic and anti-inflammatory properties in animal models of early atherosclerosis. We hypothesized that NOX4 mRNA expression is linked to protective mechanisms in CAS patients with advanced atherosclerotic lesions as well. Indeed, NOX4 mRNA expression is lower in patients with symptomatic CAS. A low NOX4 mRNA expression is associated with an increased risk of the development of clinical symptoms. In fact, NOX4 appears to be linked to plaque stability, apoptosis and plaque hemorrhage. This is supported by cleaved caspase-3 and glycophorin C and correlates inversely with plaque NOX4 mRNA expression. Even healing of a ruptured plaque appears to be connected to NOX4, as NOX4 mRNA expression correlates to fibrous cap collagen and is reciprocally related to MMP9 activity. In conclusion, low intra-plaque NOX4 mRNA expression is associated with an increased risk for symptomatic outcome and with reduced plaque stabilizing mechanisms suggesting protective effects of NOX4 in human advanced atherosclerosis., Competing Interests: Declaration of competing interest All authors do not have any conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2022
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36. Pharmacotherapies and Aortic Heme Oxygenase-1 Expression in Patients with Abdominal Aortic Aneurysm.

Author

Hofmann A, Hamann B, Klimova A, Müglich M, Wolk S, Busch A, Frank F, Sabarstinski P, Kapalla M, Nees JA, Brunssen C, Poitz DM, Morawietz H, and Reeps C

Abstract

Background: Treatment of cardiovascular risk factors slows the progression of small abdominal aortic aneurysms (AAA). Heme oxygenase-1 (HO-1) is a stress- and hemin-induced enzyme providing cytoprotection against oxidative stress when overexpressed. However, nothing is known about the effects of cardiometabolic standard therapies on HO-1 expression in aortic walls in patients with end-stage AAA., Methods: The effects of statins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), beta-blockers, diuretics, acetylsalicylic acid (ASA), and therapeutic anticoagulation on HO-1 mRNA and protein expressions were analyzed in AAA patients using multivariate logistic regression analysis and comparison of monotherapy., Results: Analysis of monotherapy revealed that HO-1 mRNA and protein expressions were higher in patients on diuretics and lower in patients on statin therapy. Tests on combinations of antihypertensive medications demonstrated that ACE inhibitors and diuretics, ARBs and diuretics, and beta-blockers and diuretics were associated with increase in HO-1 mRNA expression. ASA and therapeutic anticoagulation were not linked to HO-1 expression., Conclusion: Diuretics showed the strongest association with HO-1 expression, persisting even in combination with other antihypertensive medications. Hence, changes in aortic HO-1 expression in response to different medical therapies and their effects on vessel wall degeneration should be analyzed in future studies.

Published
2022
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37. Comparative study of the effects of cigarette smoke versus next generation tobacco and nicotine product extracts on endothelial function.

Author

Giebe S, Hofmann A, Brux M, Lowe F, Breheny D, Morawietz H, and Brunssen C

Subjects
Endothelial Cells, Endothelium, Vascular, Humans, Nicotine, Phosphatidylinositol 3-Kinases, Smoke, Smoking adverse effects, Nicotiana, Electronic Nicotine Delivery Systems, Tobacco Products
Abstract

Tobacco smoking and hemodynamic forces are key stimuli for the development of endothelial dysfunction. As an alternative to smoking, next generation tobacco and nicotine products (NGP) are now widely used. However, little is known about their potential pro-inflammatory and atherogenic effects on the endothelium. In this study, we analyzed key parameters of endothelial function after exposure to aqueous smoke extracts (AqE) of a heated tobacco product (HTP), an electronic cigarette (e-cig), a conventional cigarette (3R4F) and pure nicotine. All experiments were performed under atheroprotective high laminar or atherogenic low flow with primary human endothelial cells. Treatment with 3R4F, but not alternative smoking products, reduced endothelial cell viability and wound healing capability via the PI3K/AKT/eNOS(NOS3) pathway. Laminar flow delayed detrimental effects on cell viability by 3R4F treatment. 3R4F stimulation led to activation of NRF2 antioxidant defense system at nicotine concentrations ≥0.56 μg/ml and increased expression of its target genes HMOX1 and NQO1. Treatment with HTP revealed an induction of HMOX1 and NQO1 at dosages with ≥1.68 μg/ml nicotine, whereas e-cig and nicotine exposure had no impact. Analyses of pro-inflammatory genes revealed an increased ICAM1 expression under 3R4F treatment. 3R4F reduced VCAM1 expression in a dose-dependent manner; HTP treatment had similar but milder effects; e-cig and nicotine treatment had no impact. SELE expression was induced by 3R4F under static conditions. High laminar flow prevented this upregulation. Stimulation with laminar flow led to downregulation of CCL2 (MCP-1). From this downregulated level, only 3R4F increased CCL2 expression at higher concentrations. Finally, under static conditions, all components increased adhesion of monocytes to endothelial cells. Interestingly, only stimulation with 3R4F revealed increased monocyte adhesion under atherosclerosis-prone low flow. In conclusion, all product categories activated anti-oxidative or pro-inflammatory patterns. NGP responses were typically lower than in 3R4F exposed cells. Also, 3R4F stimulation led to an impaired endothelial wound healing and induced a pro-inflammatory phenotype compared to NGP treatment., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2021
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38. Induction of Heme Oxygenase-1 Is Linked to the Severity of Disease in Human Abdominal Aortic Aneurysm.

Author

Hofmann A, Müglich M, Wolk S, Khorzom Y, Sabarstinski P, Kopaliani I, Egorov D, Horn F, Brunssen C, Giebe S, Hamann B, Deussen A, Morawietz H, Poitz DM, and Reeps C

Subjects
Animals, Humans, Mice, Severity of Illness Index, Aortic Aneurysm, Abdominal genetics, Heme Oxygenase-1 genetics
Abstract

Background Rupture of abdominal aortic aneurysm (rAAA) is associated with high case fatality rates, and risk of rupture increases with the AAA diameter. Heme oxygenase-1 (gene HMOX1 , protein HO-1) is a stress-induced protein and induction has protective effects in the vessel wall. HMOX1 -/- mice are more susceptible to angiotensin II-induced AAA formation, but the regulation in human nonruptured and ruptured AAA is only poorly understood. Our hypothesis proposed that HO-1 is reduced in AAA and lowering is inversely associated with the AAA diameter. Methods and Results AAA walls from patients undergoing elective open repair (eAAA) or surgery because of rupture (rAAA) were analyzed for aortic HMOX1 /HO-1 expression by quantitative real-time polymerase chain reaction and Western blot. Aortas from patients with aortic occlusive disease served as controls. HMOX1 /HO-1 expression was 1.1- to 7.6-fold upregulated in eAAA and rAAA. HO-1 expression was 3-fold higher in eAAA specimen with a diameter >84.4 mm, whereas HO-1 was not different in rAAA. Other variables that are known for associations with AAA and HO-1 induction were tested. In eAAA, HO-1 expression was negatively correlated with aortic collagen content and oxidative stress parameters H 2 O 2 release, oxidized proteins, and thiobarbituric acid reactive substances. Serum HO-1 concentrations were analyzed in patients with eAAA, and maximum values were found in an aortic diameter of 55 to 70 mm with no further increase >70 mm, compared with <55 mm. Conclusions Aortic HO-1 expression was increased in eAAA and rAAA. HO-1 increased with the severity of disease but was additionally connected to less oxidative stress and vasoprotective mechanisms.

Published
2021
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39. Impact of Dietary Sodium Reduction on the Development of Obesity and Type 2 Diabetes in db/db Mice.

Author

Hofmann A, Brunssen C, Peitzsch M, Mittag J, Frenzel A, Eisenhofer G, Brown NF, Weldon SM, Reeps C, Bornstein SR, and Morawietz H

Subjects
Animals, Body Weight drug effects, Diabetes Mellitus, Type 2 metabolism, Diabetes Mellitus, Type 2 pathology, Disease Models, Animal, Disease Progression, Down-Regulation, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Obesity metabolism, Obesity pathology, Organ Size drug effects, Sodium Chloride, Dietary administration & dosage, Sodium Chloride, Dietary pharmacology, Sodium, Dietary pharmacology, Diabetes Mellitus, Type 2 diet therapy, Diet, Sodium-Restricted, Obesity diet therapy
Abstract

The impact of dietary sodium reduction on mouse models of type 2 diabetes is not well understood. Therefore, we analyzed the effect of a low-salt diet on obesity and parameters of type 2 diabetes in db/db mice. Five-week-old male db/db and lean db/m mice were fed a normal salt (0.19% Na + , NS) or a low-salt diet (<0.03% Na + , LS) for 5 weeks. Body and organ weight and parameters of glucose and insulin tolerance were analyzed. Plasma levels of steroids were determined by liquid chromatography tandem mass spectrometry. Body weight, glucose, and insulin tolerance were not affected by LS. The amount of gonadal adipose tissue showed a trend to be increased by LS whereas liver, pancreas, kidney, heart, and adrenal weight remained unaffected. LS reduced urinary sodium-to-creatinine ratio but did not affect plasma Na + levels in both genotypes. Plasma and urinary potassium-to-creatinine ratio did not differ in all groups of mice. Aldosterone as a major determinant of changes in dietary sodium remained unaffected by LS in db/db mice as well as further investigated steroid hormones. The present study showed reduced sodium-to-creatinine ratio, but no additional effects of dietary sodium reduction on major metabolic parameters and steroid levels in obese and hyper-glycemic db/db mice., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Published
2021
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40. Autophagy unleashes noncanonical microRNA functions.

Author

Santovito D, Egea V, Bidzhekov K, Natarelli L, Mourão A, Blanchet X, Wichapong K, Aslani M, Brunßen C, Horckmans M, Hristov M, Geerlof A, Lutgens E, Daemen MJAP, Hackeng T, Ries C, Chavakis T, Morawietz H, Naumann R, Hundelshausen PV, Steffens S, Duchêne J, Megens RTA, Sattler M, and Weber C

Subjects
Autophagy genetics, Caspase 3, Endothelial Cells, Humans, Atherosclerosis, MicroRNAs genetics
Abstract

MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression which act by guiding AGO (argonaute) proteins to target RNA transcripts in the RNA-induced silencing complex (RISC). This macromolecular complex includes multiple additional components ( e.g ., TNRC6A) that allow for interaction with enzymes mediating inhibition of translation or RNA decay. However, miRNAs also reside in low-molecular weight complexes without being engaged in target repression, and their function in this context is largely unknown. Our recent findings show that endothelial cells exposed to protective high-shear stress or MTORC inhibition activate the macroautophagy/autophagy machinery to sustain viability by promoting differential trafficking of MIR126 strands and by enabling unconventional features of MIR126-5p . Whereas MIR126-3p is degraded upon autophagy activation, MIR126-5p interacts with the RNA-binding protein MEX3A to form a ternary complex with AGO2. This complex forms on the autophagosomal surface and facilitates its nuclear localization. Once in the nucleus, MIR126-5p dissociates from AGO2 and establishes aptamer-like interactions with the effector CASP3 (caspase 3). The binding to MIR126-5p prevents dimerization and proper active site formation of CASP3, thus inhibiting proteolytic activity and limiting apoptosis. Disrupting this pathway in vivo by genetic deletion of Mex3a or by specific deficiency of endothelial autophagy aggravates endothelial apoptosis and exacerbates the progression of atherosclerosis. The direct inhibition of CASP3 by MIR126-5p reveals a non-canonical mechanism by which miRNAs can modulate protein function and mediate the autophagy-apoptosis crosstalk.

Published
2020
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41. NADPH oxidase 4 mediates the protective effects of physical activity against obesity-induced vascular dysfunction.

Author

Brendel H, Shahid A, Hofmann A, Mittag J, Bornstein SR, Morawietz H, and Brunssen C

Subjects
Animals, Disease Models, Animal, Endothelium, Vascular physiopathology, Male, Mice, Inbred C57BL, Mice, Knockout, Mitochondria enzymology, Mitochondria pathology, NADPH Oxidase 4 genetics, Nitric Oxide Synthase Type III metabolism, Obesity enzymology, Obesity genetics, Obesity physiopathology, Organelle Biogenesis, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism, Phosphorylation, Proto-Oncogene Proteins c-akt metabolism, Running, Signal Transduction, Vascular Diseases enzymology, Vascular Diseases genetics, Vascular Diseases physiopathology, Endothelium, Vascular enzymology, Hydrogen Peroxide metabolism, NADPH Oxidase 4 metabolism, Obesity therapy, Physical Conditioning, Animal, Vascular Diseases prevention & control, Vasoconstriction
Abstract

Aims: Physical activity is one of the most potent strategies to prevent endothelial dysfunction. Recent evidence suggests vaso-protective properties of hydrogen peroxide (H2O2) produced by main endothelial NADPH oxidase isoform 4 (Nox4) in the vasculature. Therefore, we hypothesized that Nox4 connects physical activity with vaso-protective effects., Methods and Results: Analysis of the endothelial function using Mulvany Myograph showed endothelial dysfunction in wild-type (WT) as well as in C57BL/6J/ Nox4-/- (Nox4-/-) mice after 20 weeks on high-fat diet (HFD). Access to running wheels during the HFD prevented endothelial dysfunction in WT but not in Nox4-/- mice. Mechanistically, exercise led to an increased H2O2 release in the aorta of WT mice with increased phosphorylation of eNOS pathway member AKT serine/threonine kinase 1 (AKT1). Both H2O2 release and phosphorylation of AKT1 were diminished in aortas of Nox4-/- mice. Deletion of Nox4 also resulted in lower intracellular calcium release proven by reduced phenylephrine-mediated contraction, whilst potassium-induced contraction was not affected. H2O2 scavenger catalase reduced phenylephrine-induced contraction in WT mice. Supplementing H2O2 increased phenylephrine-induced contraction in Nox4-/- mice. Exercise-induced peroxisome proliferative-activated receptor gamma, coactivator 1 alpha (Ppargc1a), as key regulator of mitochondria biogenesis in WT but not Nox4-/- mice. Furthermore, exercise-induced citrate synthase activity and mitochondria mass were reduced in the absence of Nox4. Thus, Nox4-/- mice became less active and ran less compared with WT mice., Conclusions: Nox4 derived H2O2 plays a key role in exercise-induced adaptations of eNOS and Ppargc1a pathway and intracellular calcium release. Hence, loss of Nox4 diminished physical activity performance and vascular protective effects of exercise., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Published
2020
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42. Noncanonical inhibition of caspase-3 by a nuclear microRNA confers endothelial protection by autophagy in atherosclerosis.

Author

Santovito D, Egea V, Bidzhekov K, Natarelli L, Mourão A, Blanchet X, Wichapong K, Aslani M, Brunßen C, Horckmans M, Hristov M, Geerlof A, Lutgens E, Daemen MJAP, Hackeng T, Ries C, Chavakis T, Morawietz H, Naumann R, von Hundelshausen P, Steffens S, Duchêne J, Megens RTA, Sattler M, and Weber C

Subjects
Apoptosis, Autophagy, Caspase 3, Humans, Atherosclerosis genetics, MicroRNAs genetics
Abstract

MicroRNAs (miRNAs) are versatile regulators of gene expression with profound implications for human disease including atherosclerosis, but whether they can exert posttranslational functions to control cell adaptation and whether such noncanonical features harbor pathophysiological relevance is unknown. Here, we show that miR-126-5p sustains endothelial integrity in the context of high shear stress and autophagy. Bound to argonaute-2 (Ago2), miR-126-5p forms a complex with Mex3a, which occurs on the surface of autophagic vesicles and guides its transport into the nucleus. Mutational studies and biophysical measurements demonstrate that Mex3a binds to the central U- and G-rich regions of miR-126-5p with nanomolar affinity via its two K homology domains. In the nucleus, miR-126-5p dissociates from Ago2 and binds to caspase-3 in an aptamer-like fashion with its seed sequence, preventing dimerization of the caspase and inhibiting its activity to limit apoptosis. The antiapoptotic effect of miR-126-5p outside of the RNA-induced silencing complex is important for endothelial integrity under conditions of high shear stress promoting autophagy: ablation of Mex3a or ATG5 in vivo attenuates nuclear import of miR-126-5p, aggravates endothelial apoptosis, and exacerbates atherosclerosis. In human plaques, we found reduced nuclear miR-126-5p and active caspase-3 in areas of disturbed flow. The direct inhibition of caspase-3 by nuclear miR-126-5p reveals a noncanonical mechanism by which miRNAs can modulate protein function., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Published
2020
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43. NOX4 is a major regulator of cord blood-derived endothelial colony-forming cells which promotes post-ischaemic revascularization.

Author

O'Neill KM, Campbell DC, Edgar KS, Gill EK, Moez A, McLoughlin KJ, O'Neill CL, Dellett M, Hargey CJ, Abudalo RA, O'Hare M, Doyle P, Toh T, Khoo J, Wong J, McCrudden CM, Meloni M, Brunssen C, Morawietz H, Yoder MC, McDonald DM, Watson CJ, Stitt AW, Margariti A, Medina RJ, and Grieve DJ

Subjects
Animals, Cell Movement, Cells, Cultured, Cellular Microenvironment, Disease Models, Animal, Endothelial Progenitor Cells enzymology, Fetal Blood cytology, Hindlimb, Humans, Ischemia enzymology, Ischemia genetics, Ischemia physiopathology, Mice, Inbred NOD, NADPH Oxidase 4 genetics, Reactive Oxygen Species metabolism, Recovery of Function, Signal Transduction, Endothelial Progenitor Cells transplantation, Ischemia surgery, Muscle, Skeletal blood supply, NADPH Oxidase 4 metabolism, Neovascularization, Physiologic
Abstract

Aims: Cord blood-derived endothelial colony-forming cells (CB-ECFCs) are a defined progenitor population with established roles in vascular homeostasis and angiogenesis, which possess low immunogenicity and high potential for allogeneic therapy and are highly sensitive to regulation by reactive oxygen species (ROS). The aim of this study was to define the precise role of the major ROS-producing enzyme, NOX4 NADPH oxidase, in CB-ECFC vasoreparative function., Methods and Results: In vitro CB-ECFC migration (scratch-wound assay) and tubulogenesis (tube length, branch number) was enhanced by phorbol 12-myristate 13-acetate (PMA)-induced superoxide in a NOX-dependent manner. CB-ECFCs highly-expressed NOX4, which was further induced by PMA, whilst NOX4 siRNA and plasmid overexpression reduced and potentiated in vitro function, respectively. Increased ROS generation in NOX4-overexpressing CB-ECFCs (DCF fluorescence, flow cytometry) was specifically reduced by superoxide dismutase, highlighting induction of ROS-specific signalling. Laser Doppler imaging of mouse ischaemic hindlimbs at 7 days indicated that NOX4-knockdown CB-ECFCs inhibited blood flow recovery, which was enhanced by NOX4-overexpressing CB-ECFCs. Tissue analysis at 14 days revealed consistent alterations in vascular density (lectin expression) and eNOS protein despite clearance of injected CB-ECFCs, suggesting NOX4-mediated modulation of host tissue. Indeed, proteome array analysis indicated that NOX4-knockdown CB-ECFCs largely suppressed tissue angiogenesis, whilst NOX4-overexpressing CB-ECFCs up-regulated a number of pro-angiogenic factors specifically-linked with eNOS signalling, in parallel with equivalent modulation of NOX-dependent ROS generation, suggesting that CB-ECFC NOX4 signalling may promote host vascular repair., Conclusion: Taken together, these findings indicate a key role for NOX4 in CB-ECFCs, thereby highlighting its potential as a target for enhancing their reparative function through therapeutic priming to support creation of a pro-reparative microenvironment and effective post-ischaemic revascularization., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Published
2020
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44. Soluble LOX-1: A Novel Biomarker in Patients With Coronary Artery Disease, Stroke, and Acute Aortic Dissection?

Author

Hofmann A, Brunssen C, Wolk S, Reeps C, and Morawietz H

Subjects
Acute Disease, Aortic Dissection diagnosis, Animals, Aortic Aneurysm diagnosis, Biomarkers blood, Coronary Artery Disease diagnosis, Humans, Predictive Value of Tests, Prognosis, Stroke diagnosis, Aortic Dissection blood, Aortic Aneurysm blood, Coronary Artery Disease blood, Scavenger Receptors, Class E blood, Stroke blood
Published
2020
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45. Endothelial function and gene expression in perivascular adipose tissue from internal mammary arteries of obese patients with coronary artery disease.

Author

Cybularz M, Langbein H, Zatschler B, Brunssen C, Deussen A, Matschke K, and Morawietz H

Subjects
Adiponectin genetics, Adiponectin metabolism, Aged, Body Mass Index, CD11c Antigen genetics, CD11c Antigen metabolism, Coronary Artery Bypass, Coronary Artery Disease genetics, Coronary Artery Disease metabolism, Coronary Artery Disease surgery, Dose-Response Relationship, Drug, Endothelium, Vascular drug effects, Endothelium, Vascular metabolism, Female, Gene Expression Regulation, Humans, Lectins, C-Type genetics, Lectins, C-Type metabolism, Male, Mammary Arteries drug effects, Mammary Arteries metabolism, Mammary Arteries surgery, Mannose Receptor, Mannose-Binding Lectins genetics, Mannose-Binding Lectins metabolism, Myography, Obesity diagnosis, Obesity genetics, Paracrine Communication, Receptors, Cell Surface genetics, Receptors, Cell Surface metabolism, Vasodilator Agents pharmacology, Adipose Tissue metabolism, Coronary Artery Disease physiopathology, Endothelium, Vascular physiopathology, Mammary Arteries physiopathology, Obesity physiopathology, Vasodilation drug effects
Abstract

Background and Aims: Obesity is a risk factor for endothelial dysfunction and atherosclerosis. However, perivascular adipose tissue can release adipokines and other unknown adipose-derived relaxing factors. Therefore, we investigated the impact of obesity on vascular function and expression of genes in perivascular adipose tissue from internal mammary arteries of patients with coronary artery disease undergoing coronary artery bypass grafting., Methods: The vessel function was compared between groups of patients with a body-mass index (BMI) between 25 and 30 kg/m 2 . The groups did not differ in age, gender (males), and ejection fraction. Vascular segments of internal mammary arteries were examined in a Mulvany myograph. Following preconstriction with noradrenaline, dose-response curves were assessed for relaxation with acetylcholine and sodium nitroprusside., Results: Maximum contraction in response to potassium and noradrenaline was increased in obese patients with a BMI >30 kg/m 2 . EC50 of endothelium-dependent relaxation was impaired in patients with a BMI above 25, but below 30 kg/m 2 . Sodium nitroprusside-mediated maximal relaxation was not different between study groups. Integrin alpha X chain (ITGAX/CD11c) and macrophage mannose receptor (MRC1/CD206) expression was reduced in perivascular adipose tissue of patients with a BMI above 30 kg/m 2 , while adiponectin (ADPQ) expression was increased in the same tissue., Conclusion: Our data suggest a partially reduced endothelial function in internal mammary arteries of adipose patients with a BMI between 25 and 30 kg/m 2 undergoing coronary artery bypass grafting surgery. Increased adiponectin expression in perivascular tissue might contribute to maintenance of endothelial function in obese patients with a BMI above 30 kg/m 2 ., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Published
2017
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46. Lectin-like oxidized low-density lipoprotein receptor-1 promotes endothelial dysfunction in LDL receptor knockout background.

Author

Hofmann A, Brunssen C, Poitz DM, Langbein H, Strasser RH, Henle T, Ravens U, and Morawietz H

Subjects
Animals, Aorta, Thoracic physiopathology, Aortic Diseases genetics, Aortic Diseases pathology, Aortic Diseases physiopathology, Atherosclerosis genetics, Atherosclerosis pathology, Atherosclerosis physiopathology, Blood Glucose metabolism, Cattle, Diet, Western, Disease Models, Animal, Endothelium, Vascular pathology, Endothelium, Vascular physiopathology, Genetic Predisposition to Disease, Hypercholesterolemia genetics, Hypercholesterolemia metabolism, Hypertriglyceridemia genetics, Hypertriglyceridemia metabolism, Lipids blood, Male, Mice, Inbred C57BL, Mice, Knockout, Nitric Oxide Synthase Type I genetics, Nitric Oxide Synthase Type I metabolism, Nitric Oxide Synthase Type III genetics, Nitric Oxide Synthase Type III metabolism, Phenotype, Plaque, Atherosclerotic, Receptors, LDL genetics, Scavenger Receptors, Class E genetics, Aorta, Thoracic metabolism, Aortic Diseases metabolism, Atherosclerosis metabolism, Endothelium, Vascular metabolism, Receptors, LDL deficiency, Scavenger Receptors, Class E metabolism, Vasodilation
Abstract

Objective: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major receptor for oxidized LDL in endothelial cells. LOX-1 is highly expressed in atherosclerotic plaques. The impact of LOX-1 on development of endothelial dysfunction in large vessels in absence or presence of atherosclerosis-prone conditions has not been studied to date., Methods: Mice with endothelial cell-specific LOX-1 overexpression (bLOX-1tg) were analyzed. Wild-type (WT) mice served as controls. In addition, bLOX-1tg mice were crossed with LDL receptor knockout (Ldlr -/- ) mice. All mice were fed a western-type diet (WD) or control diet (CD) for 20 weeks. Afterwards, endothelial function was analyzed ex vivo in thoracic aortas using a Mulvany myograph., Results: WD induced hypertriglyceridemia (bLOX-1tg: 1.6-fold; WT: 1.4-fold) and hypercholesterolemia (P < 0.0001) in bLOX-1tg and WT mice without HDL-elevation in bLOX-1tg mice. Gonadal fat pad weight was 1.7 and 1.2-fold increased on CD and WD in bLOX-1tg mice compared to WT. LOX-1 overexpression impaired endothelial function by 15-16% (P < 0.05) on CD and WD. Crossing bLOX-1tg mice into Ldlr -/- background strongly elevated total (∼6-fold) and LDL-cholesterol (∼9-fold) compared to WT and bLOX-1tg mice on WD. Endothelial function in response to WD was impaired in bLOX-1tg/Ldlr -/- mice (Eff max : 56.7 ± 23.0%) compared to WT (Eff max : 88.2 ± 15.8%, P < 0.001), bLOX-1tg (Eff max : 76.7 ± 12.9%, P < 0.05) and Ldlr -/- mice (Eff max : 70.1 ± 13.1%, P < 0.05). No differences between WT, bLOX-1tg and Ldlr -/- mice were detectable when comparing all genotypes., Conclusion: Endothelial LOX-1 overexpression in an atherosclerosis-prone background impairs endothelial function, proving its importance in the development of atherosclerosis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Published
2017
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47. Contribution of lectin-like oxidized low-density lipoprotein receptor-1 and LOX-1 modulating compounds to vascular diseases.

Author

Hofmann A, Brunssen C, and Morawietz H

Abstract

The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major receptor for binding and uptake of oxidized low-density lipoprotein (oxLDL) in endothelial cells. LOX-1 is also expressed in macrophages, smooth muscle cells and platelets. Following internalization of oxLDL, LOX-1 initiates a vicious cycle from activation of pro-inflammatory signaling pathways, thus promoting an increased reactive oxygen species formation and secretion of pro-inflammatory cytokines. LOX-1 plays a pivotal role in the development of endothelial dysfunction, foam cell and advanced lesions formation as well as in myocardial ischemia. Furthermore, it is known that LOX-1 plays a pivotal role in mitochondrial DNA damage, vascular cell apoptosis, and autophagy. A large number of studies provide evidence of a LOX-1's role in endothelial dysfunction, hypertension, diabetes, and obesity. In addition, novel insights into LOX-1 ligands and the activated signaling pathways have been gained. Recent studies have shown an interaction of LOX-1 with microRNA's, thus providing novel tools to regulate LOX-1 function. Because LOX-1 is increased in atherosclerotic plaques and contributes to endothelial dysfunction, several compounds were tested in vivo and in vitro to modulate the LOX-1 expression in therapeutic approaches., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Published
2017
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48. Impact of Aldosterone Synthase Inhibitor FAD286 on Steroid Hormone Profile in Human Adrenocortical Cells.

Author

Brunssen C, Hofmann A, Peitzsch M, Frenzel A, Ziegler CG, Brown NF, Weldon SM, Eisenhofer G, Willenberg HS, Bornstein SR, and Morawietz H

Subjects
Aldosterone metabolism, Angiotensin II pharmacology, Angiotensin II Type 1 Receptor Blockers pharmacology, Benzimidazoles pharmacology, Biphenyl Compounds, Cell Line, Cytochrome P-450 CYP11B2 genetics, Cytochrome P-450 CYP11B2 metabolism, Gene Expression Regulation, Enzymologic drug effects, Glucocorticoids metabolism, Humans, RNA, Messenger genetics, RNA, Messenger metabolism, Receptor, Angiotensin, Type 1 metabolism, Tetrazoles pharmacology, Adrenal Cortex cytology, Cytochrome P-450 CYP11B2 antagonists & inhibitors, Enzyme Inhibitors pharmacology, Fadrozole pharmacology, Hormones metabolism, Steroids metabolism
Abstract

Inhibition of aldosterone synthase (CYP11B2) is an alternative treatment option to mineralocorticoid receptor antagonism to prevent harmful aldosterone effects. FAD286 is the best characterized aldosterone synthase inhibitor. However, to date, no study has used sensitive liquid chromatography-tandem mass spectrometry to characterize in detail the effect of FAD286 on the secreted steroid hormone profile of adrenocortical cells. Basal aldosterone production in NCI-H295R cells was detectable and 9-fold elevated after stimulation with angiotensin II. FAD286 inhibited this increase, showing a maximal effect at 10 nmol/l. Higher concentrations of FAD286 did not further reduce aldosterone concentrations, but showed a parallel reduction in corticosterone, cortisol and cortisone levels, reflecting additional inhibition of steroid-11β-hydroxylase (CYP11B1). Pregnenolone, progesterone and 17-OH-progesterone levels remained unaffected. In conclusion, the aldosterone synthase inhibitor FAD286 lowers angiotensin II-induced aldosterone concentrations in adrenocortical cells but the relative lack of selectivity over CYP11B1 is evident at higher FAD286 concentrations., Competing Interests: Conflict of Interest: All authors declare that there is no duality of interest associated with their contribution to this manuscript., (© Georg Thieme Verlag KG Stuttgart · New York.)

Published
2017
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49. Cigarette smoke extract counteracts atheroprotective effects of high laminar flow on endothelial function.

Author

Giebe S, Cockcroft N, Hewitt K, Brux M, Hofmann A, Morawietz H, and Brunssen C

Subjects
Cell Survival drug effects, Dose-Response Relationship, Drug, Endothelium, Vascular metabolism, Gene Expression Regulation drug effects, Heme Oxygenase-1 metabolism, Human Umbilical Vein Endothelial Cells, Humans, NAD(P)H Dehydrogenase (Quinone) metabolism, NF-E2-Related Factor 2 metabolism, Oxidative Stress, Regional Blood Flow, Nicotiana adverse effects, Atherosclerosis metabolism, Endothelium, Vascular cytology, Gene Regulatory Networks drug effects, Smoke adverse effects
Abstract

Tobacco smoking and hemodynamic forces are key stimuli in the development of endothelial dysfunction and atherosclerosis. High laminar flow has an atheroprotective effect on the endothelium and leads to a reduced response of endothelial cells to cardiovascular risk factors compared to regions with disturbed or low laminar flow. We hypothesize that the atheroprotective effect of high laminar flow could delay the development of endothelial dysfunction caused by cigarette smoking. Primary human endothelial cells were stimulated with increasing dosages of aqueous cigarette smoke extract (CSEaq). CSEaq reduced cell viability in a dose-dependent manner. The main mediator of cellular adaption to oxidative stress, nuclear factor erythroid 2-related factor 2 (NRF2) and its target genes heme oxygenase (decycling) 1 (HMOX1) or NAD(P)H quinone dehydrogenase 1 (NQO1) were strongly increased by CSEaq in a dose-dependent manner. High laminar flow induced elongation of endothelial cells in the direction of flow, activated the AKT/eNOS pathway, increased eNOS expression, phosphorylation and NO release. These increases were inhibited by CSEaq. Pro-inflammatory adhesion molecules intercellular adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1), selectin E (SELE) and chemokine (C-C motif) ligand 2 (CCL2/MCP-1) were increased by CSEaq. Low laminar flow induced VCAM1 and SELE compared to high laminar flow. High laminar flow improved endothelial wound healing. This protective effect was inhibited by CSEaq in a dose-dependent manner through the AKT/eNOS pathway. Low as well as high laminar flow decreased adhesion of monocytes to endothelial cells. Whereas, monocyte adhesion was increased by CSEaq under low laminar flow, this was not evident under high laminar flow. This study shows the activation of major atherosclerotic key parameters by CSEaq. Within this process, high laminar flow is likely to reduce the harmful effects of CSEaq to a certain degree. The identified molecular mechanisms might be useful for development of alternative therapy concepts., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2017
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50. The Aldosterone Synthase Inhibitor FAD286 is Suitable for Lowering Aldosterone Levels in ZDF Rats but not in db/db Mice.

Author

Hofmann A, Brunssen C, Peitzsch M, Balyura M, Mittag J, Frenzel A, Jannasch A, Brown NF, Weldon SM, Gueneva-Boucheva KK, Eisenhofer G, Bornstein SR, and Morawietz H

Subjects
Adrenal Glands metabolism, Animals, Corticosterone biosynthesis, Cytochrome P-450 CYP11B2 metabolism, Diabetes Mellitus, Experimental pathology, Male, Mice, Obese, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Zucker, Steroid 11-beta-Hydroxylase metabolism, Aldosterone blood, Cytochrome P-450 CYP11B2 antagonists & inhibitors, Cytochrome P-450 Enzyme Inhibitors pharmacology, Diabetes Mellitus, Experimental blood, Diabetes Mellitus, Experimental enzymology, Fadrozole pharmacology
Abstract

Inhibition of aldosterone synthase is an alternative treatment option to mineralocorticoid receptor antagonism to prevent harmful aldosterone actions. FAD286 is one of the best characterized aldosterone synthase inhibitors to date. FAD286 improves glucose tolerance and increases glucose-stimulated insulin secretion in obese and diabetic ZDF rats. However, there is limited knowledge about the dose-dependent effects of FAD286 on plasma aldosterone, corticosterone, and 11-deoxycorticosterone in ZDF rats and in db / db mice, a second important rodent model of obesity and type 2 diabetes. In addition, effects of FAD286 on plasma steroids in mice and rats are controversial. Therefore, obese Zucker diabetic fatty (ZDF) rats and db / db mice were treated with FAD286 for up to 15 weeks and plasma steroids were evaluated using highly sensitive liquid chromatography-tandem mass spectrometry. In ZDF rats, FAD286 (10 mg/kg/d) treatment resulted in nearly complete disappearance of plasma aldosterone while corticosterone levels remained unaffected and those of 11-deoxycorticosterone were increased ~4-fold compared to vehicle control. A lower dose of FAD286 (3 mg/kg / d) showed no effect on plasma aldosterone or corticosterone, but 11-deoxycorticosterone was again increased ~4-fold compared to control. In contrast to ZDF rats, a high dose of FAD286 (40 mg/kg/d) did not affect plasma aldosterone levels in db / db mice although 11-deoxycorticosterone increased ~2.5-fold. A low dose of FAD286 (10 mg/kg/d) increased plasma aldosterone without affecting corticosterone or 11-deoxycorticosterone. In conclusion, the aldosterone synthase inhibitor, FAD286, lowers plasma aldosterone in obese ZDF rats, but not in obese db / db mice., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Published
2017
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