264 results on '"RENIN-angiotensin system"'
Search Results
202. Ras oncogene directs expression of a differentially sialylated, functionally altered ß1 integrin.
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Seales, Eric Clinton, Jurado, Gustavo Adolfo, Singhal, Anuj, and Bellis, Susan Lynn
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RENIN-angiotensin system , *ONCOGENES , *VIRAL genetics , *CANCER genetics , *INTEGRINS , *CELL adhesion molecules - Abstract
Intense investigation has centered on understanding the regulation of integrin cell adhesion receptors. In the present study, we propose that variant N-glycosylation represents an important mechanism for regulation of ß1, but not ß3 or ß5 integrins. We find that expression of oncogenic ras in HD3 colonocytes causes increased a2-6 sialylation of ß1 integrins, whereas expression of dominant-negative ras induces decreased a2-6 sialylation, relative to cells with wild-type ras. In contrast, neither ß3 nor ß5 integrins are a2-6 sialylated, regardless of the state of ras activation. Results from RT-PCR analyses suggest that differential integrin sialylation is due to a ras-dependent alteration in the expression of ST6Gal I, the enzyme that adds a2-6-linked sialic acids. Cells that express differentially sialylated ß1 integrins exhibit altered adhesion to collagen I (a ß1 ligand), but not to vitronectin (a ß3 or ß5 ligand). Similarly, the enzymatic removal of cell surface sialic acids from control cells alters binding to collagen, but not to vitronectin. Finally, using a cell-free receptor/ligand-binding assay, we show that purified, desialylated a1ß1 integrins have diminished collagen-binding capability, providing strong evidence that sialic acids play a causal role in regulating ß1 integrin function.Oncogene (2003) 22, 7137-7145. doi:10.1038/sj.onc.1206834 [ABSTRACT FROM AUTHOR]
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- 2003
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203. Phospholipase C? activates Ras on the Golgi apparatus by means of RasGRP1.
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Bivona, Trever G., Pérez de Castro, Ignacio, Ahearn, Ian M., Grana, Theresa M., Chiu, Vi K., Lockyer, Peter J., Cullen, Peter J., Pellicer, Angel, Cox, Adrienne D., and Philips, Mark R.
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PHOSPHOLIPASE C , *RENIN-angiotensin system , *GOLGI apparatus , *PROTEINS , *ENZYME activation - Abstract
Ras proteins regulate cellular growth and differentiation, and are mutated in 30% of cancers. We have shown recently that Ras is activated on and transmits signals from the Golgi apparatus as well as the plasma membrane[SUP1,2] but the mechanism of compartmentalized signalling was not determined. Here we show that, in response to Src-dependent activation of phospholipase C[SUBγ]1, the Ras guanine nucleotide exchange factor RasGRP1 translocated to the Golgi where it activated Ras. Whereas Ca[SUP2+] positively regulated Ras on the Golgi apparatus through RasGRP1, the same second messenger negatively regulated Ras on the plasma membrane by means of the Ras GTPase-activating protein CAPRI[SUP3]. Ras activation after T-cell receptor stimulation in Jurkat cells, rich in RasGRP1, was limited to the Golgi apparatus through the action of CAPRI, demonstrating unambiguously a physiological role for Ras on Golgi. Activation of Ras on Golgi also induced differentiation of PC12 cells, transformed fibro-blasts and mediated radioresistance. Thus, activation of Ras on Golgi has important biological consequences and proceeds through a pathway distinct from the one that activates Ras on the plasma membrane. [ABSTRACT FROM AUTHOR]
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- 2003
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204. A story of two ACEs.
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Danilczyk, Ursula, Eriksson, Urs, Crackower, Michael A., and Penninger, Josef M.
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CARDIOVASCULAR diseases , *HYPERTENSION , *MYOCARDIAL infarction , *CEREBROVASCULAR disease , *ANGIOTENSIN converting enzyme , *HEART failure , *X chromosome - Abstract
According to the World Health Organization predictions cardiovascular diseases will be the leading cause of death by the year 2020. High blood pressure is a major risk factor for myocardial infarction, cerebrovascular disease, and stroke. Modulation of the renin-angiotensin system, particularly inhibition of the angiotensin-converting enzyme (ACE), has become a prime strategy in the treatment of hypertension and heart failure. Recently the gene of a new ACE, termed ACE2, has been characterized. The ACE2 gene maps to defined quantitative trait loci on the X chromosome in three different rat models of hypertension, suggesting ACE2 as a candidate gene for hypertension. In mice the targeted disruption of ACE2 resulted in increased systemic angiotensin II levels, impaired cardiac contractility, and upregulation of hypoxia-induced genes in the heart. Since mice deficient in both ACE2 and ACE show completely normal heart function, it appears that ACE and ACE2 negatively regulate each other. The mechanisms and physiological significance of the interplay between ACE and ACE2 are not yet elucidated, but it may involve several new peptides and peptide systems. In view of drug development the increasing complexity of the renin-angiotensin system offers both challenge and opportunity to develop new and refined treatment strategies against cardiovascular diseases. [ABSTRACT FROM AUTHOR]
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- 2003
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205. Reduced heart rate variability in hypertension: associations with lifestyle factors and plasma renin activity.
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Virtanen, R, Jula, A, Kuusela, T, Helenius, H, and Voipio-Pulkki, L-M
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HYPERTENSION , *HEART beat , *LIFESTYLES , *RENIN-angiotensin system - Abstract
Limited information exists on the relations between heart rate variability, hypertension, lifestyle factors and renin-angiotensin-aldosterone system. A total of 191 newly diagnosed yet untreated hypertensive men and women, 35-54 years of age, were compared with an age- and gender-stratified random population sample of 105 normotensive men and women to find out independent determinants of heart rate variability. Heart rate variability was computed from 5-min ECG time series using the standard deviation of normal-to-normal RR intervals (SDNN), the square root of the mean of squared differences between adjacent normal RR intervals (RMSSD) and the fast Fourier transform spectral analysis. All absolute measures of heart rate variability were reduced in hypertension (P<0.001 for each, ANOVA). In multivariate regression analyses, reduced heart rate variability was independently associated with higher heart rate (P<0.001 for all absolute measures of heart rate variability), higher age (P=0.001 for SDNN, total and LF powers; P<0.001 for RMSSD and HF power) and higher mean arterial pressure (P<0.05 for total power, P<0.01 for the other absolute measures) but not with sodium and alcohol intakes, body mass index and smoking. Increased plasma renin activity (PRA) was an independent attributor of reduced HF power (P<0.05) and reduced RMSSD (P<0.01). Increased blood pressure and heart rate are associated with decreased heart rate variability without any direct effects on heart rate variability of lifestyle factors. High PRA is an independent determinant of diminished modulation of vagal activity.Journal of Human Hypertension (2003) 17, 171-179. doi:10.1038/sj.jhh.1001529 [ABSTRACT FROM AUTHOR]
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- 2003
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206. Renin-angiotensin-aldosterone system and G-protein beta-3 subunit gene polymorphisms in salt-sensitive essential hypertension.
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Pamies-Andreu, E, Ramirez-Lorca, R, Stiefel Garcia-Junco, P, Muniz-Grijalbo, O, Vallejo-Maroto, I, Garcia Morillo, S, Miranda-Guisado, M L, Ortiz, J V, and Carneado de la Fuente, J
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HYPERTENSION , *RENIN-angiotensin system , *GENETIC polymorphisms , *SALT - Abstract
Approximately 50% of hypertensive patients are salt sensitive (they increase their Blood Pressure in response to sodium intake or volume expansion). Mechanisms underlying salt sensitivity are not completely elucidated although there is evidence that they may be genetically determined. The aim of this study is to establish the relation among some genetic polymorphisms of the renin-angiotensin system (RAAS) and the beta-3 subunit of the protein G and salt sensitivity. We studied 102 essential hypertensive patients, stage 1-2 and without target organ damage. Salt sensitivity was assessed by the rapid protocol of Weinberger. We determined by polymerase Chain reaction techniques the following polymorphisms: insertion/deletion (I/D) of the angiotensin-converting enzyme (ACE), A1166C of the angiotensin II type 1 receptor (AT1R), -344C/T and intron 2 conversion (IC) of the aldosterone synthase (CYP11B2), and C825T of the beta-3 subunit of the protein G (GNB3). 41 patients (40.19%) were salt sensitive. The distribution of the different polymorphisms was similar in both groups of patients, but subjects carriers of the W allele of the CYP11B2 IC polymorphism had a greater risk for salt sensitivity as compared with no carriers (37 of 41, 90.2% vs 4 of 41, 9.8%, OR 3.02, P<0.05). Although there is no association between salt sensitivity and the different studied genotypes of the RAAS and of the GNB3, our data show a greater risk for salt sensitivity among carriers of the W allele of the CYP11B2 1C polymorphism.Journal of Human Hypertension (2003) 17, 187-191. doi:10.1038/sj.jhh.1001534 [ABSTRACT FROM AUTHOR]
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- 2003
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207. NF-κB blockade and oncogenic Ras trigger invasive human epidermal neoplasia.
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Dajee, Maya, Lazarov, Mirella, Zhang, Jennifer Y., Cai, Ti, Green, Cheryl L., Russell, Alan J., Marinkovich, M. Peter, Tao, Shiying, Lin, Qun, Kubo, Yoshiaki, and Khavari, Paul A.
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ONCOGENIC viruses , *RENIN-angiotensin system , *APOPTOSIS - Abstract
The nuclear factor NF-κB and oncogenic Ras can alter proliferation in epidermis, the most common site of human cancer. These proteins are implicated in epidermal squamous cell carcinoma in mice, however, the potential effects of altering their function are uncertain. Whereas inhibition of NF-κB enhances apoptosis in certain tumours, blockade of NF-κB predisposes murine skin to squamous cell carcinoma. Because therapeutics inhibiting Ras and NF-κB pathways are being developed to treat human cancer, it is essential to assess the effects of altering these regulators. The medical relevance of murine studies is limited, however, by differences between mouse and human skin, and by the greater ease of transforming murine cells. Here we show that in normal human epidermal cells both NF-κB and oncogenic Ras trigger cell-cycle arrest. Growth arrest triggered by oncogenic Ras can be bypassed by IκBα-mediated blockade of NF-κB, generating malignant human epidermal tissue resembling squamous cell carcinoma. Human cell tumorigenesis is dependent on laminin 5 and α6β4 integrin. Thus, IκBα circumvents restraints on growth promotion induced by oncogenic Ras and can act with Ras to induce invasive human tissue neoplasia. [ABSTRACT FROM AUTHOR]
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- 2003
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208. Endothelin-1 and vasopressin plasma levels are not associated with the insertion/deletion polymorphism of the human angiotensin I-converting enzyme gene in patients with coronary artery disease.
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Al-Fakhri, N, Linhart, R E, Philipp, M, Heidt, M, Hehrlein, F W, Gardemann, A, and Katz, N
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CORONARY disease , *RENIN-angiotensin system , *ENDOTHELINS , *VASOPRESSIN - Abstract
The objective was to investigate whether the reninangiotensin (RA) system and related peptides endothelin-1 (ET-1) and vasopressin (VP) influence the development of coronary artery disease (CAD). Angiotensin I-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism has been associated with the risk of CAD. The ACE lid polymorphism determines ACE activity, but plasma levels of other RA system components remain unchanged. However, ET-1 and VP production could be increased by RA system-dependent stimulation, continually promoted by paracrine stimulation and sustained by neointimal growth. ET-1 and VP have not been associated with the ACE l/D polymorphism so far. The present study investigated the association of the ACE lid polymorphism with plasma concentrations of ET-1 and VP, as well as with renin, angiotensin-II (AT-II) and ACE activity in 98 Caucasian individuals with CAD. ACE l/D polymorphism showed no association with plasma levels of VP, ET-1, AT-II or renin. These parameters were also not associated taking into consideration different patient variables, such as diabetes mellitus, hypertension or severity of CAD. Only plasma ACE activity was associated with the D allele. In conclusion, the ACE I/D polymorphism could not be related to plasma concentrations of VP, ET-1, renin or AT-II, but as previously demonstrated, it could only be related to ACE activity in patients with CAD. Differences in ACE activity between ACE lid genotype subgroups are probably compensated within the RA system itself or within non-ACE pathways, so that plasma concentrations of the related peptides ET-1 and VP remain unaffected. [ABSTRACT FROM AUTHOR]
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- 2003
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209. Association of polymorphisms of the renin–angiotensin system and bradykinin B2 receptor with ACE-inhibitor-related cough.
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Mukae, S, Itoh, S, Aoki, S, Iwata, T, Nishio, K, Sato, R, and Katagiri, T
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GENETIC polymorphisms , *RENIN-angiotensin system - Abstract
The use of angiotensin-converting enzyme (ACE) inhibitors to treat hypertension has recently increased. However, their use is associated with a persistent dry cough in a significant percentage of such patients. The present study was designed to assess the contribution of polymorphisms as a genetic marker of ACE-inhibitor-related cough in a Japanese hypertensive population. Genotyping was carried out in 190 patients, 70 with cough and 120 without cough, who had been treated with ACE inhibitors. Polymorphisms of ACE insertion/ deletion (I/D), angiotensin II type 1 receptor (1166A/C), type 2 receptor (3123C/A), and bradykinin B2 receptor (-58T/C, exon 1, I/D), were analyzed in these subjects. The TT genotype and T allele of bradykinin B2 receptor (-58T/C) were identified at a significantly higher frequency in the cough (+) patients than in the cough (-) patients. This difference was even more pronounced in women. However, there was no significant relationship between polymorphisms of ACE, angiotensin II receptors, or bradykinin B2 receptor exon 1, and occurrence of ACE-inhibitor-related cough. The transcriptional activity of the bradykinin B2 receptor promoter is involved in the occurrence of cough, and this new marker may provide a valuable tool to detect patients at risk of developing this side effect of ACE inhibitors. In conclusion, Susceptibility to develop cough is associated with a genetic variant of the bradykinin B2 receptor promoter; thus, it may be possible to identify those patients who will develop this adverse reaction to ACE inhibitors in advance. [ABSTRACT FROM AUTHOR]
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- 2002
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210. CDK4 coexpression with Ras generates malignant human epidermal tumorigenesis.
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Lazarov, Mirella, Kubo, Yoshiaki, Cai, Ti, Dajee, Maya, Tarutani, Masahito, Lin, Qun, Fang, Min, Tao, Shiying, Green, Cheryl L., and Khavari, Paul A.
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RENIN-angiotensin system , *CYCLIN-dependent kinases - Abstract
Ras acts with other proteins to induce neoplasia. By itself, however, strong Ras signaling can suppress proliferation of normal cells. In primary epidermal cells, we found that oncogenic Ras transiently decreases cyclin-dependent kinase (CDK) 4 expression in association with cell cycle arrest in G1 phase. CDK4 co-expression circumvents Ras growth suppression and induces invasive human neoplasia resembling squamous cell carcinoma. Tumorigenesis is dependent on CDK4 kinase function, with cyclin D1 required but not sufficient for this process. In facilitating escape from G1 growth restraints, Ras and CDK4 alter the composition of cyclin D and cyclin E complexes and promote resistance to growth inhibition by INK4 cyclin-dependent kinase inhibitors. These data identify a new role for oncogenic Ras in CDK4 regulation and highlight the functional importance of CDK4 suppression in preventing uncontrolled growth. [ABSTRACT FROM AUTHOR]
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- 2002
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211. Heritability of plasma renin activity and plasma concentration of angiotensinogen and angiotensin-converting enzyme.
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Vinck, W.J., Fagard, R.H., Vlietinck, R., and Lijnen, P.
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RENIN-angiotensin system , *ANGIOTENSIN converting enzyme - Abstract
The purpose of the present investigation was to describe the relative impact of genes and environment on the variance of the plasma constituents of the renin angiotensin system. We ascertained 56 male and 80 female adult same-sex twin pairs from the Flemish population. Plasma renin activity (PRA), the concentration of angiotensinogen (AGT) and angiotensinconverting enzyme (ACE) were measured, and path analysis was applied, after transformation toward normality. For PRA and AGT significant heritability was only detected in the male subgroup, with heritability estimates of 66% and 90%, respectively. Angiotensin-converting enzyme concentration was determined by additive genes for 43% of its variance, by shared environmental influences for 42%, and by specific environmental influences for 15%. The high heritability found for AGT is compatible with the results of earlier studies linking the M235T polymorphism of the angiotensinogen gene to plasma AGT levels. For PRA, we are the first to show significant heritability. Our results regarding ACE confirm the findings in other populations. [ABSTRACT FROM AUTHOR]
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- 2002
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212. Efficacy of eprosartan in combination with HCTZ in patients with essential hypertension.
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Sachse, A., Verboom, C., and Jager, B.
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RENIN-angiotensin system , *REGULATION of blood pressure - Abstract
This randomised, double-blind study was designed to investigate the efficacy of a once-daily (OD) combination of the AT[sub 1] receptor blocker, eprosartan 600 mg, and the thiazide diuretic, hydrochlorothiazide (HCTZ) 12.5 mg, in patients with mild to moderate hypertension (sitting diastolic blood pressure (sitDBP) ≥98 mm Hg and ≤114 mm Hg) not adequately controlled with eprosartan 600 mg OD. A total of 494 patients entered the open-label monotherapy run-in phase, which consisted of eprosartan 600 mg OD for 3 weeks. Patients who responded to monotherapy were not eligible to enter the randomised phase of the study and were withdrawn. The remaining 309 patients were then randomised to either eprosartan 600 mg plus HCTZ 12.5 mg OD or to continue on eprosartan 600 mg OD. In the eprosartan plus HCTZ combination group, both sitDBP and sitting systolic blood pressure (sitSBP) were significantly reduced compared with the eprosartan monotherapy group. In addition, the response rate was higher in the combination group compared with the monotherapy group. There were no significant effects on reduction of sitDBP due to gender, prior use of antihypertensives or baseline severity of hypertension. The tolerability profile for the combination group was similar to that for the monotherapy group. Headache was the most frequent adverse event in both treatment groups. The majority of adverse events were mild to moderate in intensity. In this study of patients who were unresponsive to eprosartan monotherapy for 3 weeks, a combination product of eprosartan 600 mg and HCTZ 12.5 mg was shown to be an effective and well tolerated treatment. [ABSTRACT FROM AUTHOR]
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- 2002
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213. Apoptosis coincident with the differentiation of skeletal myoblasts is delayed by caspase 3 inhibition and abrogated by MEK-independent constitutive Ras signaling.
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Dee, K., Freer, M., Mei, Y., and Weyman, C.M.
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APOPTOSIS , *RENIN-angiotensin system - Abstract
We demonstrate that during 23A2 skeletal myoblast differentiation, between 30-35% of the population apoptose. Both differentiation and apoptosis are controlled by the variables of cell density and time and these variables are inversely related. in response to conditions that permit both differentiation and apoptosis of parental 23A2 myoblasts, myoblasts rendered differentiation-defective by constitutive Ras signaling (A2:HRas myoblasts) do not apoptose. This is not merely a consequence of their differentiation-defective phenotype since myoblasts rendered differentiation-defective by expression of E1A (A2:E1A myoblasts) still apoptose. Although signaling through MEK is important to the survival of proliferating parental 23A2 myoblasts, constitutive signaling through MEK is not responsible for the survival of A2:H-Ras myoblasts. Finally, we demonstrate that caspase 3 is activated and that pharmacological inhibition of caspase 3 activity delays apoptosis without affecting differentiation. Abrogating apoptosis without affecting differentiation could be a useful approach to improve the efficacy of myoblast transfer in the treatment of muscular dystrophies. [ABSTRACT FROM AUTHOR]
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- 2002
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214. Inhibition of protein farnesylation enhances the chemotherapeutic efficacy of the novel geranylgeranyltransferase inhibitor BAL9611 in human colon cancer cells.
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Paolo, A Di, Danesi, R, Caputo, S, Macchia, M, Lastella, M, Boggi, U, Mosca, F, Marchetti, A, and Tacca, M Del
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RENIN-angiotensin system , *PROTEINS , *CELL proliferation - Abstract
Proteins belonging to the ras superfamily are involved in cell proliferation of normal and neoplastic tissues. To be biologically active, they require post-translational isoprenylation by farnesyl-transferase and geranylgeranyl-transferase. Enzyme inhibition by drugs may thus represent a promising approach to the treatment of cancer. Therefore, the combined effect of BAL9611, a novel inhibitor of geranylgeranylation, and manumycin, a farnesyl-transferase inhibitor, was evaluated on the SW620 human colon cancer cell line which harbours a mutated K-ras gene. BAL9611 and manumycin dose-dependently inhibited SW620 cell growth with 50% inhibitory concentration (IC[SUB50]) of 0.47 ± 0.03 and 5.24 ± 1.41) μM (mean ± SE), respectively. The isobologram analysis performed at the IC[SUB50] (level revealed that the) combined treatment was highly synergistic with respect to cell growth inhibition. BAL9611 and manumycin were able to inhibit the geranylgeranylation of p21rhoA and farnesylation of p21ras; both drugs inhibited p42ERK2/MAPK phosphorylation, but their combination was more effective than either drug alone. Moreover, the enhanced inhibition of cell growth in vitro by the BAL9611-manumycin combination was also observed in vivo in CD nu/nu female mice xenografted with SW620 tumours. Finally, both drugs were able to induce cell death by apoptosis in vitro and in vivo, as demonstrated by perinuclear chromatin condensation, cytoplasm budding and nuclear fragmentation, and interoligonucleosomal DNA digestion. In conclusion, the inhibition of protein farnesylation enhances the chemotherapeutic effect of BAL9611 in vitro and in vivo in a synergistic fashion, as a result of the impairment of post-translational isoprenylation of proteins and phosphorylation of p42ERK2/MAPK, whose activation is associated with post-translational geranylgeranylation and farnesylation of p21rhoA and p21ras. [ABSTRACT FROM AUTHOR]
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- 2001
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215. Polymorphisms of the renin-angiotensin system in patients with multifocal renal arterial fibromuscular dysplasia.
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Bofinger, A, Hawley, C, Fisher, P, Daunt, N, Stowasser, M, and Gordon, R
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GENETIC polymorphisms , *RENIN-angiotensin system , *HYPERTENSION - Abstract
Fibromuscular dysplasia (FMD) is an important cause of renal artery stenosis, particularly in young females. Polymorphisms of the renin-angiotensin (RA) system have been implicated in the pathogenesis of hypertension and atherosclerotic vascular disease, and may play a role in the development of FMD. Examination of polymorphisms by PCR for angiotensin-converting enzyme (ACE) I/D, angiotensin II type 1 receptor AT[SUB1]R) A1166C and angiotensinogen (AGT) M235T and T174M was undertaken in 43 patients with typical multifocal renal arterial FMD (MF-FMD) and in 89 controls. The age of MF-FMD patients at the time of diagnosis of hypertension did not differ (38.6 ± 11.1 years vs 35.5 ± 10.3 years, P = 0.12) from controls and the proportion (95% vs 86%, P = 0.14) of females was similar. Allele frequencies did not differ significantly between groups, except that MF-FMD patients had a significantly higher frequency of the ACE I allele than control subjects (0.62 vs 0.47, P = 0.026). Since the ACE I allele is associated with lower circulating ACE levels and possibly lower tissue levels of angiotensin II (Ang II), and since Ang II modulates vascular smooth muscle cell growth and synthetic activity, the I allele might predispose to defective remodelling of the arterial media, and thus to the development of MF-FMD. This contrasts with atherosclerotic renal artery stenosis, coronary stent restenosis and carotid intimal thickening, which are diseases affecting the arterial intima, and which are associated with increased frequency of the D allele. [ABSTRACT FROM AUTHOR]
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- 2001
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216. Magnetic resonance detects changes in phosphocholine associated with Ras activation and inhibition in NIH 3T3 cells.
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Ronen, S M, Jackson, L E, Beloueche, M, and Leach, M O
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RENIN-angiotensin system , *MAGNETIC resonance - Abstract
Ras is frequently mutated in cancer, and novel therapies are being developed to target Ras signalling. To identify non-invasive surrogate markers of Ras activation and inhibition, we used [sup31]P magnetic resonance spectroscopy (MRS) and investigated NIH 3T3 cells compared to a mutant ras transfected counterpart. The MR spectra indicated that phosphocholine (PC) levels increased significantly from 3 ± 2 fmol cell[sup-1]in NIH 3T3 cells to 13 ± 4 fmol cell[sup-1]in the transfected cells. The PC/NTP ratio increased significantly from 0.3 ± 0.1 to 0.7 ± 0.3. This could not be explained by either a faster proliferation rate or by alterations in cell cycle distribution. Both cell lines were treated with simvastatin, 17-AAG and R115777, agents which inhibit Ras signalling. Cell proliferation was inhibited in both cell lines. The spectrum of NIH 3T3 cells was not affected by treatment. In contrast, in the ras transfected cells growth inhibition was associated with an average 35 ± 5% drop in PC levels and a comparable drop in PC/NTP. Thus the MRS visible increase in phosphocholine is associated with Ras activation, and response to treatment is associated with partial reversal of phosphocholine increase in ras transfected cells. MRS might therefore be a useful tool in detecting Ras activation and its inhibition following targeted therapies. [ABSTRACT FROM AUTHOR]
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- 2001
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217. Blockade of the renin-angiotensin-aldosterone system with combination angiotensin receptor antagonist and ACE inhibitor therapy: Observations from Val-HeFT and CALM.
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Chin, B S P and Lip, G Y H
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HEART failure , *RENIN-angiotensin system - Abstract
Presents a commentary on the blockade of the renin-angiotensin-aldosterone system (RAAS) by combining angiotensin receptor antagonist and angiotensin converting enzyme (ACE) inhibitor therapy for heart failure. Effect of blockade of angiotensin II; Metigenic actions of tissue-based RAAS; Impact of the combination therapy on diabetics.
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- 2001
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218. The renin-angiotensin system in the year 2000.
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Nicholls, M G and Robertson, J I S
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RENIN-angiotensin system , *ANGIOTENSINS , *HYPERTENSION - Abstract
Focuses on renin-angiotensin system. Discovery of renin; Physiological and pathological significance of renin-angiotensin system in hypertension; Range of actions of renin-angiotensin system.
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- 2000
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219. The dominant negative H-ras mutant, N116Y, suppresses growth of metastatic human pancreatic cancer cells in the liver of nude mice.
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Takeuchi, M, Shichinohe, T, Senmaru, N, Miyamoto, M, Fujita, H, Takimoto, M, Kondo, S, Katoh, H, and Kuzumaki, N
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PANCREATIC cancer , *RENIN-angiotensin system , *LIVER metastasis - Abstract
In pancreatic cancer, the mutation of c-K-ras is a critical event of tumor growth and metastasis. We have previously demonstrated a dominant negative effect of N116Y on the growth of pancreatic cancer cells. To evaluate the potential of N116Y for suppressing the metastatic growth of pancreatic tumor cells, we made a replication-deficient recombinant N116Y adenovirus driven by the carcinoembryonic antigen (CEA) promoter (Ad CEA-N116Y). We demonstrated that the expression of N116Y, growth inhibition, and apoptotic death induction were all specific to pancreatic cancer cell lines (PCI-35 and PCI-43) that were promoter positive, whereas no growth retardation was observed in human embryonic pancreas-derived cell line 1C3D3 after Ad CEA-N116Y infection. We examined the effect of Ad CEA-N116Y on the metastatic growth of PCI-43 colonies in liver, which was generated by tumor injection into the spleen of nude mice. The results showed that Ad CEA-N116Y effectively reduced the number of metastatic colonies without any complication by injecting intrasplenically 5 days after tumor cell inoculation. Thus, N116Y can selectively suppress the metastatic growth of pancreatic tumor cell by using the CEA promoter-driven adenovirus vector indicating that N116Y gene therapy may be potentially useful for the treatment of pancreatic cancer patients with liver micrometastasis. [ABSTRACT FROM AUTHOR]
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- 2000
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220. Effects of transplantation on the renin angiotensin system (RAS).
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Farge, D and Julien, J
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RENIN-angiotensin system , *TRANSPLANTATION of organs, tissues, etc. , *CYCLOSPORINE , *HYPERTENSION - Abstract
Hypertension in organ transplant recipients is associated with several functional modifications of the renin angiotensin system (RAS), which varies according to the type of transplanted organs (kidney, heart, liver or bone marrow) and the immunosuppressive regimen. Before transplantation, chronic organ failure is associated with direct and indirect stimulation of both systemic and local RASs. After transplantation, cyclosporin per se is the major determinant of hypertension. It induces stimulation of both systemic and local RAS via direct and indirect effects within the kidney and peripheral vessels. In kidney transplant recipients, ischaemia from the native kidneys and from the graft, due to acute or chronic rejection, also contributes to RAS stimulation. In cardiac transplant recipients, several haemodynamic parameters, abnormal cardiorenal neuroendocrine reflex mechanism and other hormonal systems (ANF, AVP, cathecholamines) stimulate the RAS. [ABSTRACT FROM AUTHOR]
- Published
- 1998
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221. POSTERS TOPIC F: CHARACTERISATION OF MUTATIONS.
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MEDICAL research , *DUCHENNE muscular dystrophy , *RENIN-angiotensin system , *MEMBRANE proteins , *CARDIOVASCULAR diseases , *GENETICS - Abstract
The article presents abstracts of medical research. They include "Multiple endocrine neoplasia type II B," "Identification of a 58-bp insertion coupled with a duplication of exon 44 in the dystrophin transcripts of a Duchenne Muscular Dystrophy patient," and "Studies of a contribution of the renin-angiotensin system into genetic susceptibility to cardiovascular disorders in a Moscow population."
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- 1999
222. Evidence for a local renin angiotensin system in primary cultured human preadipocytes.
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Schling, P, Mallow, H, Trindl, A, and Löffler, G
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FAT cells , *RENIN-angiotensin system - Abstract
OBJECTIVE: To investigate whether human preadipocytes possess a complete functional renin angiotensin system. MEASUREMENTS: Gene expression of angiotensinogen, renin, renin binding protein, angiotensin converting enzyme (ACE) and angiotensin II (ang II) receptor type 1 in human preadipocytes; ACE protein and ang II production of human adipose tissue stromal cells differentiated or not in primary culture. RESULTS: All genes mentioned above were found to be expressed in human preadipocytes. ACE was translated into protein as detected by western blot. Ang II was secreted both by undifferentiated preadipocytes and immature adipocytes, and its production was significantly elevated in differentiated cells. CONCLUSIONS: Preadipocytes from human adipose tissue express a functional renin angiotensin system (RAS). [ABSTRACT FROM AUTHOR]
- Published
- 1999
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223. Plasma renin activity could be a useful predictor of left ventricular hypertrophy in essential hypertensives.
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Koga, M, Sasaguri, M, Miura, S, Tashiro, E, Kinoshita, A, Ideishi, M, and Arakawa, K
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BLOOD pressure measurement , *CHOLESTEROL , *ELECTROCARDIOGRAPHY , *RENIN-angiotensin system - Abstract
To clarify the ability of clinical and laboratory parameters to reflect target organ damage, especially left ventricular hypertrophy (LVH), we investigated which of these parameters might correlate to LVH as determined by electrocardiographic voltage at the first clinic visit in 108 (53 males and 55 females, average age 52 ± 10 years) untreated essential hypertensives. The sum of the amplitude of the S wave in lead V[SUB1] plus that of the R wave in lead V[SUB5] or V[SUB6] (SV[SUB1] + R(V[SUB5], V[SUB6])) was correlated with blood pressure in both males and females. In subjects with LVH (SV[SUB1] + R(V[SUB5], V[SUB6])≥3.5mV), a stepwise multiple regression analysis revealed that SV[SUB1] + (R(V[SUB5], V[SUB6]) was associated with plasma renin activity (PRA) in both males and females, and with creatinine concentration (Cr) in males. These results suggest that PRA at the first visit could be a useful predictor of LVH in patients with essential hypertension. [ABSTRACT FROM AUTHOR]
- Published
- 1998
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224. The importance of the renin-angiotensin system in cardiovascular disease.
- Author
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Nicholls, M G, Richards, A M, and Agarwal, M
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RENIN-angiotensin system , *HYPERTENSION , *DIABETES - Abstract
The renin-angiotensin system is central to the pathophysiology of a number of cardiovascular disorders. Most obviously this is so with renin secreting tumours, but the system is of central importance in other disorders such as scleroderma renal crisis and most cases of malignant hypertension. Activation of the renin-angiotensin system in unilateral renal artery stenosis is pivotal to the development of hypertension and the disturbances in electrolyte and volume balance -- most particularly in the hyponatraemic-hypertensive syndrome. Likewise, stimulation of the renin-angiotensin system is an important contributor, amongst many other systems, to the pathophysiology of cardiac failure. In diabetic nephropathy, the renin-angiotensin system is often suppressed as gauged by circulating levels of renin, yet it appears to make an important contribution to the progressive decline in renal function. Much less clear is the role of the renin-angiotensin system in essential hypertension insofar as it contributes to the level of blood pressure, to the development of left ventricular hypertrophy, and in the evolution of complications such as stroke and myocardial infarction. Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors has contributed to our understanding of the role of this system in cardiovascular disease. The advent of selective angiotensin II type-1 receptor blockers will further increase knowledge in this area. [ABSTRACT FROM AUTHOR]
- Published
- 1998
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225. Pharmacokinetics of candesartan after single and repeated doses of candesartan cilexetil in young and elderly healthy volunteers.
- Author
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Hübner, R., Högemann, A. M., Sunzel, M., and Riddell, J. G.
- Subjects
- *
PHARMACOKINETICS , *DRUG dosage , *RENIN-angiotensin system , *BLOOD plasma , *ANGIOTENSIN I , *ANGIOTENSIN II - Abstract
Candesartan cilexetil is rapidly and completely hydrolysed to the active compound candesartan during absorption from the gastrointestinal tract. Candesartan is a potent, long-acting, selective angiotensin II AT1 receptor blocker. The pharmacokinetics of candesartan were investigated after single and repeated once-daily doses of candesartan cilexetil in the dose range 2-16 mg in both younger (19-40 years) and elderly (65-78 years) healthy volunteers in five studies. Blood pressure, heart rate, and hormones associated with the renin-angiotensin system, and safety of candesartan cilexetil administration were also assessed. Placebo comparisons were made in four studies. Frequent blood samples were collected after the first single dose of candesartan cilexetil, and during the last dosing interval after 1 week repeated once-daily administration. Serum and plasma were analysed for candesartan cilexetil, candesartan and its inactive metabolite, CV-15959, as well as angiotensin I and II, aldosterone, plasma renin activity (PRA) and angiotensin-converting enzyme (ACE) activity. The AUC and Cmax of candesartan showed dose-proportional increases in the dose range of 2-16 mg candesartan cilexetil after both single and repeated once-daily tablet intake, indicating linear pharmacokinetics in both younger and elderly healthy subjects. The pharmacokinetics did not change on repeated dosing and, as expected from the half-life of candesartan of approximately 9 h in younger subjects, there was almost no accumulation after repeated once-daily dosing. The time to peak candesartan concentrations after tablet intake was consistently approximately 4 h at all dose levels. Both Cmax and AUC of candesartan were increased after single and repeated once-daily dosing in the elderly compared to younger subjects by approximately 50%. However, no accumulation after repeated once-daily dosing were seen in the elderly. The half-life of candesartan in the elderly (9-12 h) was somewhat longer than in the younger healthy adult volunteers (approximately 9 h) and no gender-related differences in the disposition of candesartan were observed. Serum concentrations of CV-15959 were much lower than candesartan, and reached peak serum concentrations later, about 4-9 h after dose intake. The elimination of CV-15959 was somewhat slower than that of candesartan. Candesartan cilexetil, the prodrug to candesartan, was not measurable in serum. No differences in ACE activity or serum aldosterone concentrations were observed between subjects receiving candesartan cilexetil and placebo tablets. Plasma angiotensin I and II concentrations and PRA were augmented after single doses and further increased after 1 week repeated candesartan cilexetil dosing. Single and repeated doses of candesartan cilexetil were well tolerated in the younger and elderly volunteers. Only mild adverse events were recorded, with `headache' as the most commonly reported event, and no increase in the number of reported adverse events was observed with higher doses of candesartan cilexetil. No clinically significant changes in respect to vital signs, physical examination, ECG, and clinical laboratory tests were observed. [ABSTRACT FROM AUTHOR]
- Published
- 1997
226. Do we need angiotensin II antagonists to treat hypertensive patients?
- Author
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Ménard, J., Chatellier, G., and Azizi, M.
- Subjects
- *
ANGIOTENSIN-receptor blockers , *HYPERTENSION , *ANGIOTENSIN converting enzyme , *RENIN-angiotensin system , *DRUG dosage , *PEPTIDASE - Abstract
The article discusses the efficacy of angiotensin II antagonists in antihypertensive treatment. Clinical tests have found that angiotensin II antagonists can possibly achieve a greater degree of specificity in blocking the renin angiotensin system. It was also found with arterial hypertension do not demonstrate conclusively that angiotensin II antagonists are more effective than angiotensin-converting enzyme inhibitors at the dosages usually used.
- Published
- 1997
227. Transgenic rats as models for hypertension.
- Author
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Pinto-Sietsma, S-J and Paul, M
- Subjects
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HYPERTENSION , *TRANSGENIC animals , *RATS , *RENIN-angiotensin system , *ENDOTHELINS - Abstract
Focuses on the use of transgenic rats models to study gene function in hypertension. Rats expressing components of the renin-angiotensin system and endothelin system; Advantages of models; Limitations of models; Comparison between transgenic rats and mice.
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- 1997
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228. Impact of the renin-angiotensin-aldosterone system on blood pressure response to intravenous enalaprilat in patients with hypertensive crises.
- Author
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Hirschl, M M, Binder, M, Bur, A, Herkner, H, Woisetschläger, C, Bieglmayer, C, and Laggner, A N
- Subjects
- *
BLOOD pressure , *RENIN-angiotensin system - Abstract
The purpose of the study was to evalute the impact of the renin-angiotensin-aldosterone (RAA) system on blood pressure (BP) response in patients with hypertensive emergencies and urgencies treated with intravenous enalaprilat. Thirty-five patients with a systolic BP (SBP) >210 mm Hg and/or diastolic BP (DBP) >110 mm Hg received 5 mg enalaprilat intravenously. The extent of systolic and DBP reduction was correlated with pretreatment concentrations of angiotensin II (ANG II) (SBP: r = -0.47; P = 0.006; DBP: r = -0.55; P = 0.001) and plasma renin activity (PRA) (SBP: r = -0.49; P = 0.003; DBP: r = 0.48; P = 0.007). Non-responders to enalaprilat exhibited significant lower pretreatment levels of PRA, angiotensin-converting enzyme (ACE) and ANG II compared to responders (PRA: 5.5 ± 3.7 vs 1.1 ± 2.2 ng/ml/h, P < 0.001; ACE: 12.8 ± 3.5 vs 8.2 ± 4.8 U/l, P = 0.003; ANG II:8.7 ± 6.2 vs 5.0 ± 3.8 pg/ml, P = 0.04). In patients with severe hypotension following application of enalaprilat ANG II concentrations were significantly higher compared to patients with mean arterial BP reduction <25% (12.3 ± 6.7 vs 5.6 ± 4.0 pg/ml, P = 0.013). These data indicate that PRA and ANG II are the major determinants for BP response to enalaprilat. This relation between BP response and RAA system activity have important clinical implications for the treatment of patients with severe hypertension. Primary therapeutic failure indicates that the RAA system contributes very little to the hypertensive status of the patient. Thus, repetitive application on an ACE inhibitor in primary responders is clinically unhelpful and may result in an unnecessary delay of an effective BP reduction. In contrast, high ANG II concentrations are associated with a considerable risk for severe hypotension after enolanalaprilat application. Therefore, the status of the RAA system determines the efficacy as well as the safety of ACE inhibitor treatment in... [ABSTRACT FROM AUTHOR]
- Published
- 1997
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229. Population characteristics and the modulation of the renin-angiotensin system in the treatment of hypertension.
- Author
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Weir, M R
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RENIN-angiotensin system , *HYPERTENSION , *THERAPEUTICS , *ANTIHYPERTENSIVE agents - Abstract
Clinical evidence supports the concept that there are racial differences in response to antihypertensive drugs. The high frequency of dietary salt sensitivity and low plasma renin activity (PRA) in hypertensives of African-American descent has been suggested by some to be the critical factor which explains this difference. Evaluation of the antihypertensive response of African-Americans to diuretics and calcium channel blockers compared to other drugs suggest that they may have an advantage in controlling blood pressure (BP). However, these comparative clinical trials have not assessed dietary salt consumption, the salt sensitivity status of the participants, nor have they explored full titration dosages of the comparative drugs. For these reasons, there is insufficient information to state with certainty whether some drugs may be more effective than others as mono-therapy in controlling BP in hypertensives of African-American descent. [ABSTRACT FROM AUTHOR]
- Published
- 1997
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230. Ras-dependent apoptosis correlates with persistent activation of stress-activated protein kinases and induction of isoform(s) of Bcl-x.
- Author
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Yu, Ker, Chen, Ying-Nan P, Ravera, Christina P, Bayona, William, Nalin, Carlo M, and Mallon, Robert
- Subjects
- *
RENIN-angiotensin system , *APOPTOSIS , *PROTEIN kinases - Abstract
Ras proteins are signal transducers for many cellular responses. However, it is not well established whether Ras-signaling also contributes to apoptosis. We have constructed H-RasR12-transformed Rat1 fibroblasts using tetracycline operator/repressor (TetO/TetR)-based conditional vectors. Rat1/TetO-RasR12 (Rat1-Ras) cells produced high levels of H-RasR12 protein and exhibited oncogenic transformation. Treatment of Rat1-Ras cells with 0.1% serum triggered massive apoptosis. Rat1-Ras cells expressed increased basal activities of extracellular response kinase (ERK) and p46/p54 stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK). Interestingly, Ras-dependent apoptosis correlated with further persistent activation of both p46 and p54 SAPK/JNK and concurrent inhibition of ERK. Differential modulation of SAPK/JNK and ERK was not detected in tetracycline-treated cells that did not commit apoptosis. Furthermore, two Bcl-x related proteins of 15 kDa and 18 kDa were highly induced in apoptotic Rat1-Ras cells. Our results establish a direct role for Ras in apoptosis, and suggest a functional relationship between H-Ras, SAPK/JNK, ERK and Bcl-x in regulating apoptosis. [ABSTRACT FROM AUTHOR]
- Published
- 1997
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231. Augmented transcripts of kidney injury markers and renin angiotensin system in urine samples of overweight young adults.
- Author
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Rivera, Patricia, Miranda, Catalina, Roldán, Nicole, Guerrero, Aaron, Olave, Javier, Cárdenas, Pilar, Nguyen, Quynh My, Kassan, Modar, and Gonzalez, Alexis A.
- Subjects
- *
KIDNEY injuries , *BIOMARKERS , *RENIN-angiotensin system , *OBESITY , *YOUNG adults , *URINALYSIS - Abstract
Obesity has been firmly established as a major risk factor for common disease states including hypertension, type 2 diabetes mellitus, and chronic kidney disease. Increased body mass index (BMI) contributes to the activation of both the systemic and intra-tubular renin angiotensin systems (RAS), which are in turn associated with increased blood pressure (BP) and kidney damage. In this cross-sectional study, 43 subjects of normal or increased body weight were examined in order to determine the correlation of BMI or body fat mass (BFM) with blood pressure, fasting blood glucose (FBG), and urinary kidney injury markers such as interleukin-18 (IL-18), connective tissue growth factor (CTGF), neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1 (KIM-1). Our results showed that: (1) subjects with increased body weight showed significantly higher BP, BFM, total body water and metabolic age; (2) BMI was positively correlated to both systolic (R2 = 0.1384, P = 0.01) and diastolic BP (R2 = 0.2437, P = 0.0008); (3) BFM was positively correlated to DBP (R2 = 0.1232, P = 0.02) and partially correlated to urine protein (R2 = 0.047, P = 0.12) and FBG (R2 = 0.07, P = 0.06); (4) overweight young adults had higher urinary mRNA levels of renin, angiotensinogen, IL-18 and CTGF. These suggest that BMI directly affects BP, kidney injury markers, and the activation of the intra-tubular RAS even in normotensive young adults. Given that BMI measurements and urine analyses are non-invasive, our findings may pave the way to developing a new and simple method of screening for the risk of chronic kidney disease in adults. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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232. Angiotensin dependent and angiotensin independent protective effects of renin-b in H9c2 cells after anoxia.
- Author
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Wanka, Heike, Lutze, Philipp, Staar, Doreen, Bracke, Katharina, Golchert, Janine, and Peters, Jörg
- Subjects
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RENIN-angiotensin system , *REGULATION of blood pressure , *WATER-electrolyte balance (Physiology) , *HYPERTENSION risk factors , *NECROSIS , *APOPTOSIS - Abstract
The renin-angiotensin system is known to regulate blood pressure as well as water- and electrolyte balance. An activated RAS is involved in the development of hypertension and hypertension-related organ damage. Thus, inhibitors of the RAS are protective and markedly increasing the life span of patients. In contrast, renin transcripts have been discovered encoding a cytoplasmatic renin isoform, termed renin-b, which is not harmful but may be even protective. Here we demonstrate that depletion of renin-b encoding transcripts by small interference RNA decreased ATP levels and increased basal necrosis as well as apoptosis rates. Furthermore, renin-b depletion potentiated the anoxia-induced increase of necrosis rates. Vice versa, overexpression of renin-b prevented the anoxia-induced increase of caspase-mediated apoptosis rates. Besides, cells overexpressing renin-b exhibited even reduced mitochondrial mediated apoptosis rates under anoxia, when compared with normoxic conditions, as indicated by Annexin V labeling. However, whereas the protective effect of renin-b on caspase-mediated apoptosis was completely blocked by the renin inhibitor CH732, the effect on mitochondrial-mediated apoptosis was not affected by CH732 at all. From these data we conclude that renin-b overexpression mediates cardioprotective effects under anoxia with respect to mitochondrial induced apoptosis angiotensin-independently, but with respect to caspase induced apoptosis likely in an angiotensin-dependent manner. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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233. Connecting the renin-angiotensin-aldosterone system with sudden death.
- Author
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Luft, Friedrich C.
- Subjects
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ASPARTIC proteinases , *SUDDEN death , *RENIN-angiotensin system , *ENZYMES , *MORTALITY , *ANGIOTENSIN II - Abstract
The article presents the author's comments on the article related to mechanisms responsible for sudden death influenced by the renin-angiotensin system by S. Iravanian and colleagues. He states that by blocking the renin-angiotensin aldosterone system, sudden death can be reduced. Further he discusses the experiment of author where he has used mice with overexpression of angiotensinconverting enzyme (ACE).
- Published
- 2011
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234. How is SOS activated? Let us count the ways.
- Author
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Findlay, Greg M. and Pawson, Tony
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RENIN-angiotensin system , *G proteins , *GUANOSINE triphosphate , *HISTONES , *MOLECULAR biology - Abstract
The article discusses how SOS is activated on signaling events in cellular functions. It cites that SOS is a guanine nucleotide exchange factor needed in activating RENIN-angiotensin system (Ras) and depends on minor phospholipid component of cell membranes, including phosphatidylinositol-4, 5-bisphosphate (PIP2) and GTP-bound Ras. Moreover, it asserts that these signals work together in autoinhibitory DH-PH domains.
- Published
- 2008
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235. The renin–angiotensin and “drinking” behavior.
- Author
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Luft, Friedrich
- Subjects
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ALCOHOLISM , *RENIN-angiotensin system , *PHYSIOLOGICAL effects of angiotensins , *HYPERTENSION , *DRINKING behavior , *ENZYMES - Abstract
The article presents an author's perspective concerning the relation between alcohol intake or drinking behavior with the renin-angiotensin (Ang) system or hypertension. There have been studies that recognized the association between hypertension and alcohol abuse, and procedures conducted that decrease the renin-Ang system resulted to increase in ethanol consumption. A study about angiotensin-coverting enzyme (ACE) and the Ang II receptor expression in various brain regions is also cited.
- Published
- 2007
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236. Connectivity mapping of glomerular proteins identifies dimethylaminoparthenolide as a new inhibitor of diabetic kidney disease.
- Author
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Klein, Julie, Caubet, Cécile, Camus, Mylène, Makridakis, Manousos, Denis, Colette, Gilet, Marion, Feuillet, Guylène, Rascalou, Simon, Neau, Eric, Garrigues, Luc, Thillaye du Boullay, Olivier, Mischak, Harald, Monsarrat, Bernard, Burlet-Schiltz, Odile, Vlahou, Antonia, Saulnier-Blache, Jean Sébastien, Bascands, Jean-Loup, and Schanstra, Joost P.
- Subjects
- *
DIABETIC nephropathies , *DIABETES complications , *KIDNEY disease treatments , *RENIN-angiotensin system , *KIDNEY glomerulus , *RAMIPRIL , *ACE inhibitors , *ANIMAL models in research - Abstract
While blocking the renin angiotensin aldosterone system (RAAS) has been the main therapeutic strategy to control diabetic kidney disease (DKD) for many years, 25–30% of diabetic patients still develop the disease. In the present work we adopted a systems biology strategy to analyze glomerular protein signatures to identify drugs with potential therapeutic properties in DKD acting through a RAAS-independent mechanism. Glomeruli were isolated from wild type and type 1 diabetic (Ins2Akita) mice treated or not with the angiotensin-converting enzyme inhibitor (ACEi) ramipril. Ramipril efficiently reduced the urinary albumin/creatine ratio (ACR) of Ins2Akita mice without modifying DKD-associated renal-injuries. Large scale quantitative proteomics was used to identify the DKD-associated glomerular proteins (DKD-GPs) that were ramipril-insensitive (RI-DKD-GPs). The raw data are publicly available via ProteomeXchange with identifier PXD018728. We then applied an in silico drug repurposing approach using a pattern-matching algorithm (Connectivity Mapping) to compare the RI-DKD-GPs's signature with a collection of thousands of transcriptional signatures of bioactive compounds. The sesquiterpene lactone parthenolide was identified as one of the top compounds predicted to reverse the RI-DKD-GPs's signature. Oral treatment of 2 months old Ins2Akita mice with dimethylaminoparthenolide (DMAPT, a water-soluble analogue of parthenolide) for two months at 10 mg/kg/d by gavage significantly reduced urinary ACR. However, in contrast to ramipril, DMAPT also significantly reduced glomerulosclerosis and tubulointerstitial fibrosis. Using a system biology approach, we identified DMAPT, as a compound with a potential add-on value to standard-of-care ACEi-treatment in DKD. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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- View/download PDF
237. Letter to the Editor regarding "A microanalytical capillary electrophoresis mass spectrometry assay for quantifying angiotensin peptides in the brain".
- Author
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Danser, A. H. Jan and Poglitsch, Marko
- Subjects
- *
NEUROPEPTIDES , *CAPILLARY electrophoresis , *MASS spectrometry , *RENIN-angiotensin system , *ANGIOTENSIN converting enzyme , *ANGIOTENSIN I , *SMALL interfering RNA - Abstract
Lombard-Banek et al. describe a novel microanalytical capillary electrophoresis-coupled mass spectrometry (MS) approach for angiotensin detection in brain nuclei [[1]]. Thus, before concluding that there is "local" angiotensin production, the authors should either remove blood, or, preferably (since blood removal will not take away receptor-bound blood-derived angiotensin), treat the mice with liver-targeted angiotensinogen siRNA, thus suppressing angiotensin generation in blood only [[4]]. [Extracted from the article]
- Published
- 2019
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238. Change in blood pressure predicts regression of cardiac hypertrophy in patients of African ancestry receiving agents influencing the renin–angiotensin system.
- Author
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Libhaber, E. N., Norton, G. R., Libhaber, C. D., Candy, G. P., Woodiwiss, A. J., Sliwa, K., Essop, M. R., and Sareli, P.
- Subjects
- *
BLOOD pressure , *CARDIAC hypertrophy , *RENIN-angiotensin system , *ALDOSTERONE , *HEART diseases - Abstract
Report that change in blood pressure predicts regression of cardiac hypertrophy in patients of African ancestry receiving agents influencing the renin angiotensin system. Extent of blood pressure changes; Reductions in left ventricular mass.
- Published
- 2005
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239. BRAF mutations in non-Hodgkin's lymphoma.
- Author
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Lee, J. W., Yoo, N. J., Soung, Y. H., Kim, H. S., Park, W. S., Kim, S. Y., Lee, J. H., Park, J. Y., Cho, Y. G., Kim, C. J., Ko, Y. H., Kim, S. H., Nam, S. W., Lee, J. Y., and Lee, S. H.
- Subjects
- *
LYMPHOMAS , *TUMOR growth , *MUTAGENESIS , *CANCER , *CELL proliferation , *RENIN-angiotensin system , *AMINO acids , *PROTEINS - Abstract
Ras proteins control signalling pathways that are key regulators of several aspects of normal cell growth and malignant transformation. BRAF, which encodes an RAF family member in the downstream pathway of RAS, is somatically mutated in a number of human cancers. The activating mutation of BRAF is known to play a role in tumour development. As there have been no data on the BRAF mutation in non-Hodgkin's lymphoma (NHL), we analysed the genomic DNAs from 164 NHLs by polymerase chain reaction (PCR)-based single-strand conformation polymorphism (SSCP) for the detection of somatic mutations of BRAF (exons 11 and 15). Overall, we detected BRAF mutations in four NHLs (2.4%). Whereas most BRAF mutations in human cancers involved V599 of BRAF, all of the four BRAF mutations in the NHLs involved other amino acids (one G468A, two G468R and one D593G). To our knowledge, this is the first report on BRAF mutation in NHL, and the data indicate that BRAF is occasionally mutated in NHL, and suggest that BRAF mutation may contribute to the tumour development in some NHLs.British Journal of Cancer (2003) 89, 1958-1960. doi:10.1038/sj.bjc.6601371 www.bjcancer.com [ABSTRACT FROM AUTHOR]
- Published
- 2003
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240. A new, easily generated mouse model of diabetic kidney fibrosis.
- Author
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He, Xiaolin, Zhang, Tianzhou, Tolosa, Monica, Goru, Santosh Kumar, Chen, Xiaolan, Misra, Paraish S., Robinson, Lisa A., and Yuen, Darren A.
- Subjects
- *
DIABETIC nephropathies , *ANIMAL models in research , *RENIN-angiotensin system , *HYPERGLYCEMIA , *HYPERTENSION , *GLOMERULAR filtration rate - Abstract
Our understanding of diabetic kidney disease pathogenesis has been hampered by the lack of easily generated pre-clinical animal models that faithfully recapitulate critical features of human disease. While most standard animal models develop manifestations of early stage diabetic injury such as hyperfiltration and mesangial matrix expansion, only a select few develop key late stage features such as interstitial fibrosis and reduced glomerular filtration rate. An underlying theme in these late stage disease models has been the addition of renin-angiotensin system hyperactivation, an important contributor to human disease pathogenesis. Widespread use of these models has been limited, however, as they are either labour intensive to generate, or have been developed in the rat, preventing the use of the many powerful genetic tools developed for mice. Here we describe the Akita+/− Ren+/− mouse, a new, easily generated murine model of diabetic kidney disease that develops many features of late stage human injury, including not only hyperglycemia, hypertension, and albuminuria, but also reduced glomerular filtration rate, glomerulosclerosis, and interstitial fibrosis. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
241. TGR(mREN2)27 rats develop non-alcoholic fatty liver disease-associated portal hypertension responsive to modulations of Janus-kinase 2 and Mas receptor.
- Author
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Klein, Sabine, Kleine, Carola-Ellen, Pieper, Andrea, Granzow, Michaela, Gautsch, Sebastian, Himmit, Mimoun, Kahrmann, Katharina, Schierwagen, Robert, Uschner, Frank Erhard, Magdaleno, Fernando, Naoum, Maria Eleni, Kristiansen, Glen, Walther, Thomas, Bader, Michael, Sauerbruch, Tilman, and Trebicka, Jonel
- Subjects
- *
FATTY liver , *PORTAL hypertension , *JANUS kinases , *LIVER disease treatment , *RENIN-angiotensin system , *MESSENGER RNA - Abstract
Prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Resulting fibrosis and portal hypertension, as a possible secondary event, may necessitate treatment. Overexpression of mouse renin in the transgenic rat model, TGR(mREN2)27, leads to spontaneous development of NAFLD. Therefore, we used TGR(mREN2)27 rats as a model of NAFLD where we hypothesized increased susceptibility and investigated fibrosis and portal hypertension and associated pathways. 12-week old TGR(mREN2)27 rats received either cholestatic (BDL) or toxic injury (CCl4 inhalation). Portal and systemic hemodynamic assessments were performed using microsphere technique with and without injection of the Janus-Kinase 2 (JAK2) inhibitor AG490 or the non-peptidic Ang(1-7) agonist, AVE0991. The extent of liver fibrosis was assessed in TGR(mREN2)27 and wild-type rats using standard techniques. Protein and mRNA levels of profibrotic, renin-angiotensin system components were assessed in liver and primary hepatic stellate cells (HSC) and hepatocytes. TGR(mREN2)27 rats developed spontaneous, but mild fibrosis and portal hypertension due to the activation of the JAK2/Arhgef1/ROCK pathway. AG490 decreased migration of HSC and portal pressure in isolated liver perfusions and in vivo. Fibrosis or portal hypertension after cholestatic (BDL) or toxic injury (CCl4) was not aggravated in TGR(mREN2)27 rats, probably due to decreased mouse renin expression in hepatocytes. Interestingly, portal hypertension was even blunted in TGR(mREN2)27 rats (with or without additional injury) by AVE0991. TGR(mREN2)27 rats are a suitable model of spontaneous liver fibrosis and portal hypertension but not with increased susceptibility to liver damage. After additional injury, the animals can be used to evaluate novel therapeutic strategies targeting Mas. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
242. Angiotensin-(1-7) exerts a protective action in a rat model of ventilator-induced diaphragmatic dysfunction.
- Author
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Zambelli, Vanessa, Sigurtà, Anna, Rizzi, Laura, Zucca, Letizia, Delvecchio, Paolo, Bresciani, Elena, Torsello, Antonio, and Bellani, Giacomo
- Subjects
- *
MUSCULAR atrophy , *WESTERN immunoblotting , *RENIN-angiotensin system , *NEUROMUSCULAR blocking agents , *DIAPHRAGM (Anatomy) , *ANGIOTENSINS , *ARTIFICIAL respiration , *ANGIOTENSIN-receptor blockers , *MUSCLE contraction - Abstract
Background: Ventilator-induced diaphragmatic dysfunction (VIDD) is a common event during mechanical ventilation (MV) leading to rapid muscular atrophy and contractile dysfunction. Recent data show that renin-angiotensin system is involved in diaphragmatic skeletal muscle atrophy after MV. In particular, angiotensin-II can induce marked diaphragm muscle wasting, whereas angiotensin-(1-7) (Ang-(1-7)) could counteract this activity. This study was designed to evaluate the effects of the treatment with Ang-(1-7) in a rat model of VIDD with neuromuscular blocking agent infusion. Moreover, we studied whether the administration of A-779, an antagonist of Ang-(1-7) receptor (Mas), alone or in combination with PD123319, an antagonist of AT2 receptor, could antagonize the effects of Ang-(1-7).Methods: Sprague-Dawley rats underwent prolonged MV (8 h), while receiving an iv infusion of sterile saline 0.9% (vehicle) or Ang-(1-7) or Ang-(1-7) + A-779 or Ang-(1-7) + A-779 + PD123319. Diaphragms were collected for ex vivo contractility measurement (with electric stimulation), histological analysis, quantitative real-time PCR, and Western blot analysis.Results: MV resulted in a significant reduction of diaphragmatic contractility in all groups of treatment. Ang-(1-7)-treated rats showed higher muscular fibers cross-sectional area and lower atrogin-1 and myogenin mRNA levels, compared to vehicle treatment. Treatment with the antagonists of Mas and Ang-II receptor 2 (AT2R) caused a significant reduction of muscular contractility and an increase of atrogin-1 and MuRF-1 mRNA levels, not affecting the cross-sectional fiber area and myogenin mRNA levels.Conclusions: Systemic Ang-(1-7) administration during MV exerts a protective role on the muscular fibers of the diaphragm preserving muscular fibers anatomy, and reducing atrophy. The involvement of Mas and AT2R in the mechanism of action of Ang-(1-7) still remains controversial. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
243. FGF-21, a newcomer in the field of hypertension research.
- Author
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Eto, K
- Subjects
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FIBROBLAST growth factors , *HYPERTENSION , *RENIN-angiotensin system , *TRIGLYCERIDES , *BLOOD pressure - Abstract
The author discusses the fibroblast growth factor (FGF)-21 hormone and its association with hypertension. The author mentions that levels of FGF-21 are regulated independently by renin-angiotensin system of systemic blood pressure lowering. The author notes that the inclusion of triglyceride levels as an explanatory variable weakened the association between hypertension and FGF-21 levels.
- Published
- 2013
- Full Text
- View/download PDF
244. Structural biology: On stress and pressure.
- Author
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Sigmund, Curt D.
- Subjects
- *
ANGIOTENSINS , *PEPTIDE hormones , *RENIN-angiotensin system , *REACTIVE oxygen species , *OXIDATIVE stress , *BLOOD pressure - Abstract
The article discusses the conformational changes of angiotensinogen peptide hormone mediated by oxidative stress in the area cleaved by renin which increases blood pressure. It states that reactive oxygen species produces a common thread binding to cellular receptors induced by diverse cellular process of angiotensin. Findings of the study by A. Zhou and colleagues indicate the influence of reactive oxygen species in rennin-angiotensin system and its pro-hypertensive impacts.
- Published
- 2010
- Full Text
- View/download PDF
245. Improving vagal activity ameliorates cardiac fibrosis induced by angiotensin II: in vivo and in vitro.
- Author
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Liu, Jin-Jun, Huang, Ning, Lu, Yi, Zhao, Mei, Yu, Xiao-Jiang, Yang, Yang, Yang, Yong-hua, and Zang, Wei-Jin
- Subjects
- *
HEART fibrosis , *ANGIOTENSIN II , *RENIN-angiotensin system , *ABDOMINAL aorta , *PROTEIN expression , *HEART beat , *BAROREFLEXES , *FIBROBLASTS - Abstract
Cardiac remodeling is characterized by overactivity of the renin-angiotensin system (RAS) and withdrawal of vagal activity. We hypothesized that improving vagal activity could attenuate cardiac fibrosis induced by angiotensin II (Ang II) in vivo and in vitro. Rats were subjected to abdominal aorta constriction (AAC) with or without pyridostigmine (PYR) (31 mg/kg/d). After 8 weeks, PYR significantly decreased Ang II level, AT1 protein expression, and collagen deposition in cardiac tissue and improved heart rate variability, baroreflex sensitivity and cardiac function, which were abolished by atropine. In vitro, treatment of cardiac fibroblasts (CFs) with Ang II (10−7 M) increased cell proliferation, migration, transformation, and secretory properties, which were significantly diminished by acetylcholine (ACh, 10−6 M). Subsequently, Ang II significantly increased collagen type I expression as well as metalloproteinase (MMP)-2 expression and activity. Transforming growth factor (TGF)-β1 expression and Smad3 phosphorylation presented a similar trend. Notably, the knockdown of the acetylcholine M2 receptor by siRNA could abolish ACh anti-fibrotic action. These data implicated cholinesterase inhibitor can increase vagal activity and reduce local Ang II level, and ACh inhibit Ang II pro-fibrotic effects. Our findings suggested that the parasympathetic nervous system can serve as a promising target for cardiac remodeling treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
246. An old couple: the renin–angiotensin system (RAS) and the Journal of Molecular Medicine (JMolMed).
- Author
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Ganten, Detlev, Bader, Michael, and Jürgensen, Jan Steffen
- Subjects
- *
RENIN-angiotensin system , *CLINICAL trials - Abstract
The article discusses various reports published within the issue, including one on renin-angiotensin system (RAS) and another on clinical trials of renin inhibitor aliskiren.
- Published
- 2008
- Full Text
- View/download PDF
247. What’s new in the renin-angiotensin system?
- Author
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Smith, A. I. and Turner, A. J.
- Subjects
- *
RENIN-angiotensin system , *ENZYMES , *CATALYSIS , *CRYSTALS , *HOMEOSTASIS , *CELLULAR control mechanisms , *BIOLOGICAL transport - Abstract
. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
248. Signal transduction: Life on Mars, cellularly speaking.
- Author
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Di Fiore, Pier Paolo
- Subjects
- *
CELLULAR signal transduction , *PROTEINS , *RENIN-angiotensin system , *GOLGI apparatus - Abstract
Cellular communication relies on the emission of signals by one cell and their detection by receptors at the outer plasma membrane of another; the receptors then send a message inwards towards the nucleus. Inside the cell, proteins of the Ras family are key binary switches that are turned from 'off ' to 'on' by these receptor-transduced incoming stimuli, and propagate signals further downstream. Bivona and co-workers confirm that one Ras protein, Ha-Ras, is also activated on the Golgi apparatus inside the cell, and they show that it is not only biologically active there, but is the sole effective form of Ras in certain settings. The Golgi is involved in protein secretion, and thereby controls how signals get out of the cell. The discovery that, through Ras, it also regulates how they get in is, from a signalling viewpoint, as unexpected as life on Mars.
- Published
- 2003
- Full Text
- View/download PDF
249. Age and CHADS2 Score Predict the Effectiveness of Renin-Angiotensin System Blockers on Primary Prevention of Atrial Fibrillation.
- Author
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Hung, Chen-Ying, Hsieh, Yu-Cheng, Li, Cheng-Hung, Huang, Jin-Long, Lin, Ching-Heng, and Wu, Tsu-Juey
- Subjects
- *
RENIN-angiotensin system , *ATRIAL fibrillation prevention , *ANGIOTENSIN converting enzyme , *ANGIOTENSIN-receptor blockers , *ARRHYTHMIA - Abstract
Renin-angiotensin system (RAS) blockers have potential protective effects against atrial fibrillation (AF). The purpose of this study was to determine if patient characteristics and underlying co-morbidities could predict the efficacy of RAS blockers in AF prevention. Patients aged ≥ 45 years with hypertension were identified from the Taiwan National Health Insurance Research Database. After propensity-score matching, a total of 22,324 patients were included in this study. Risk of new-onset AF in RAS blockers users and non-users was estimated. During up to 10 years of follow-up, 1,475 patients experienced new-onset AF. Overall, RAS blockers reduced the risk of AF by 36% (adjusted HR 0.64; 95% CI 0.58 to 0.71; p < 0.001). Subgroup analysis showed that RAS blockers use was beneficial for AF prevention in patients aged ≥ 55 years or with a CHADS2 score of 1, 2, or 3. The therapy provided no obvious beneficial effect for AF prevention in those aged less than 55 years or with a CHADS2 score ≥ 4. In conclusion, RAS blockers reduced the risk of new-onset AF in patients aged ≥ 55 years or with a CHADS2 score of 1, 2, or 3, but not in patients aged less than 55 years or with a CHADS2 score ≥ 4. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
250. Dietary Sodium Suppresses Digestive Efficiency via the Renin-Angiotensin System.
- Author
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Weidemann, Benjamin J., Voong, Susan, Morales-Santiago, Fabiola I., Kahn, Michael Z., Ni, Jonathan, Littlejohn, Nicole K., Claflin, Kristin E., Burnett, Colin M.L., Pearson, Nicole A., Lutter, Michael L., and Grobe, Justin L.
- Subjects
- *
PHYSIOLOGICAL effects of sodium , *SODIUM content of food , *DIGESTIVE organs , *RENIN-angiotensin system , *OBESITY risk factors , *PHYSICAL activity , *FOOD habits - Abstract
Dietary fats and sodium are both palatable and are hypothesized to synergistically contribute to ingestive behavior and thereby obesity. Contrary to this hypothesis, C57BL/6J mice fed a 45% high fat diet exhibited weight gain that was inhibited by increased dietary sodium content. This suppressive effect of dietary sodium upon weight gain was mediated specifically through a reduction in digestive efficiency, with no effects on food intake behavior, physical activity, or resting metabolism. Replacement of circulating angiotensin II levels reversed the effects of high dietary sodium to suppress digestive efficiency. While the AT1 receptor antagonist losartan had no effect in mice fed low sodium, the AT2 receptor antagonist PD-123,319 suppressed digestive efficiency. Correspondingly, genetic deletion of the AT2 receptor in FVB/NCrl mice resulted in suppressed digestive efficiency even on a standard chow diet. Together these data underscore the importance of digestive efficiency in the pathogenesis of obesity, and implicate dietary sodium, the renin-angiotensin system, and the AT2 receptor in the control of digestive efficiency regardless of mouse strain or macronutrient composition of the diet. These findings highlight the need for greater understanding of nutrient absorption control physiology, and prompt more uniform assessment of digestive efficiency in animal studies of energy balance. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
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