Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II is the major effector peptide of the renin-angiotensin system, and it exerts its physiologic functions via a G protein-coupled cell surface receptor called AT1. We found that in rat aortic smooth muscle cells, angiotensin II stimulated the formation of Ras-GTP, Ras-Raf-1 complex formation, and the tyrosine phosphorylation of two important Ras GTPase-activating proteins (GAPs), p120 Ras-GAP and p190 Rho-GAP. Electroporation of anti-pp60c-src antibody into cultured, adherent smooth muscle cells blocked the angiotensin II stimulation of Ras-GAP and Rho-GAP tyrosine phosphorylation. In contrast electroporation of antibodies against c-Yes or c-Fyn had no effect. Anti-pp60c-src antibody also blocked angiotensin II-stimulated Ras activation and Ras-Raf-1 complex formation. These data strongly suggest that a G protein-coupled receptor such as the AT1 receptor can activate the Ras protein cascade via the tyrosine kinase pp60c-src.
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PMID:Angiotensin II controls p21ras activity via pp60c-src. 862 2

Angiotensin (Ang) II is capable of producing inflammatory changes by signals through its AT1 receptor. Reactive oxygen species production, adhesion molecule expression, chemokines, and other mediators are involved. Nuclear factor-kappaB (NK-kappaB) and activator protein 1 (AP-1) are two of the transcription factors activating the responsible genes. We have studied Ang II-independent modulating effects in a double transgenic rat model harboring the human renin and angiotensinogen genes. We have recently focused on the protective effects of HMG-CoA reductase inhibition and review these data here. We found that cerivastatin decreased mortality, lowered blood pressure, preserved renal function, decreased cardiac hypertrophy, and inhibited the entire chain of inflammatory events. Furthermore, NF-kappaB and AP-1 activation was sharply attenuated. We also observed that cerivastatin blocked ERK1/2 phosphorylation in vivo and in vitro. Cerivastatin also inhibited phorbol ester-transmitted events in vascular smooth muscle cells. Because Rho, a member of the Ras protein superfamily is important to Ang II-dependent and -independent vascular smooth muscle signaling events, we suggest that cerivastatin may act by inhibiting the prenylation, membrane anchoring, and subsequent activation of Ras proteins. These data may in part explain cholesterol-independent, HMG-CoA reductase-related, protective effects.
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PMID:Modulating angiotensin II-induced inflammation by HMG Co-A reductase inhibition. 1141 66

Chronic hypertension is a major risk factor for numerous cardiovascular disorders and is strongly associated with stroke. Hypertension alters cerebral vascular structure and may have profound deleterious effects on cerebral vascular function, the underlying mechanisms of which are still not well understood. Recent findings have led to important developments in our understanding of novel areas of cerebral vascular biology. This review briefly examines new evidence for physiologic and pathologic roles of K(+) channels, the renin-angiotensin system and reactive oxygen species, and Rho and Rho-kinase in regulation of cerebral vascular tone.
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PMID:Novel mechanisms contributing to cerebral vascular dysfunction during chronic hypertension. 1173 99

The coexistence of hypercholesterolaemia and diabetes dramatically and synergistically increases the risk of microvascular and macrovascular complications in patients. A single unifying mechanism of increased production of reactive oxygen species (ROS) by angiotensin II (Ang II) may serve as a causal link between hyperglycaemia and hypercholesterolaemia and many of the major pathways responsible for atherogenic and diabetic disorders. Several lines of evidence suggest a crucial role for Ang II-mediated oxidative stress in the pathogenesis of hyperglycaemia- and hypercholesterolemia-associated endothelial dysfunction. Endothelial dysfunction in these scenarios may be due to impaired nitric oxide (NO) synthesis and/or inactivation of endothelium-derived NO by ROS. That Ang II plays an important role in the development of atherosclerosis and glomerulosclerosis is supported by numerous studies indicating that angiotensin receptor blockers (ARBs) retard the progression of these diseases in both experimental animal models and humans. Evidence indicates that Ang II contributes to atherogenesis at both transcriptional and translational levels by upregulating adhesion molecule mRNA and protein synthesis. The recent demonstration of Ang II AT(2) receptors in the adult kidney and their potential to oppose the vasoconstrictive, antinatriuretic, and profibrotic properties of AT(1) receptors suggests that the balance of intrarenal AT(1) and AT(2) receptors may be important in determining the cellular responses to Ang II in diabetic nephropathy. Results of these studies suggest that hypercholesterolaemia and hyperglycaemia can induce a pro-inflammatory response within coronary arteries and the kidney glomerulus. This response involves production of well described macrophage chemotactic and adhesion molecules, which results in macrophage recruitment and the development of acute and chronic injury. Glomerular macrophage recruitment in experimental diabetes occurs via Ang II-stimulated monocyte chemoattractant protein (MCP)-1 expression, suggesting that the renin-angiotensin system is an important regulator of local MCP-1 expression, and strongly implicating macrophage recruitment and activation in the pathogenesis of early diabetic glomerular injury. Diabetes-associated vascular complications may also involve an activation of the nuclear factor (NF)-kappaB by hyperglycaemia. NF-kappaB activation is related to AT(1) receptor-mediated pathways, and is believed to be dependent on activation of the Rho proteins belonging to the superfamily of low molecular weight guanosine triphosphatases (GTPases) that regulate intracellular signalling. Preincubation of vascular smooth muscle cells with insulin doubled NF-kappaB transactivation stimulated by Ang II and hyperglycaemia, suggesting a potential mechanism for crosstalk between the renin-angiotensin system and hyperglycaemia. Taken together, these data suggest that activation of the renin-angiotensin system is a mechanism for the initiation and progression of inflammatory cell infiltration found in early changes common to both hypercholesterolaemia and hyperglycaemia. While the base of information regarding ARBs in high-risk patients with diabetes and hypercholesterolemia is lacking, preclinical and pilot trial data suggest that the ARBs are reno- and vasculoprotective in these patients. Therapeutic blockade of Ang II AT(1) receptors in diabetic and hypercholesterolaemic humans by ARBs, with concomitant elevation in plasma and tissue Ang II levels, may provide vascular and renal protection not only by reducing AT(1) receptor-mediated pro-oxidative effects, but also by unopposed AT(2) receptor stimulation.
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PMID:[Pathophysiological and clinical implications of AT(1) and AT(2) angiotensin II receptors in metabolic disorders: hypercholesterolaemia and diabetes]. 1203 87

Angiotensin II (AngII), the major effector peptide of renin-angiotensin system (RAS), is now recognized as a growth factor that regulates cell growth and fibrosis, besides being a physiological mediator restoring circulatory integrity. In the last few years, a large number of experimental studies has further demonstrated that AngII is involved in key events of the inflammatory process. Here, we summarize the wide variety of AngII functions and discuss them in relation with the inflammatory cascade. AngII increases vascular permeability (via the release of prostaglandins and vascular endothelial cell growth factor or rearrangement of cytoskeletal proteins) that initiates the inflammatory process. AngII could contribute to the recruitment of inflammatory cells into the tissue through the regulation of adhesion molecules and chemokines by resident cells. Moreover, AngII could directly activate infiltrating immunocompetent cells, including chemotaxis, differentiation and proliferation. Recent data also suggest that RAS activation could play a certain role even in immunologically-induced inflammation. Transcriptional regulation, predominantly via nuclear factor-kappaB (NF-kappaB) and AP-1 activation, and second mediator systems, such as endothelin-1, the small G protein (Rho) and redox-pathways are shown to be involved in the molecular mechanism by which AngII exerts those functions. Finally, AngII participates in tissue repair and remodeling, through the regulation of cell growth and matrix synthesis. In summary, recent data support the hypothesis that RAS is key mediator of inflammation. Further understanding of the role of the RAS in this process may provide important opportunities for clinical research and treatment of inflammatory diseases.
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PMID:Inflammation and angiotensin II. 1267 74

Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), the rate-limiting enzyme of cholesterol synthesis. In recent years, statins have become the major choice of treatment for hypercholesterolemia. Emerging evidence from both animal and human studies indicates that mechanisms independent of cholesterol lowering effects contribute to the observed clinical benefits of statins. The anti-hypertrophy effect of statins on the cardiac tissue represents one of such mechanisms. The beneficial effects of statins on cardiac hypertrophy and cardioprotection may be attributed to their functional influences on small G proteins such as Ras and Rho, resulting in an increase of endogenous nitric oxide (NO), reduction of oxidative stress, inhibition of inflammatory reaction, and decrease of the renin-angiotensin system activity as well as C-reactive protein (CRP) levels in cardiac tissues. Recent findings from in vitro and in vivo studies of statins on cardioprotective effects are summarized in this review. The unveiled novel mechanisms support the use of statins as the new mainstay therapeutic agents for various cardiovascular diseases and complications.
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PMID:Perspectives on the cardioprotective effects of statins. 1287 Nov 30

Very little is known regarding the mechanisms of action of angiotensin II (Ang II) or the consequences of Ang II-dependent hypertension in the cerebral circulation. We tested the hypothesis that Ang II produces constriction of cerebral arteries that is mediated by activation of AT1A receptors and Rho-kinase. Basilar arteries (baseline diameter approximately 130 microm) from mice were isolated, cannulated and pressurized to measure the vessel diameter. Angiotensin II was a potent constrictor in arteries from male, but not female, mice. Vasoconstriction in response to Ang II was prevented by an inhibitor of Rho-kinase (Y-27632) in control mice, and was reduced by approximately 85% in mice deficient in expression of AT1A receptors. We also examined the chronic effects of Ang II using a model of Ang II-dependent hypertension, mice which overexpress human renin (R+) and angiotensinogen (A+). Responses to the endothelium-dependent agonist acetylcholine were markedly impaired in R+A+ mice (P<0.01) compared with controls, but were restored to normal by a superoxide scavenger (PEG-SOD). A-23187 (another endothelium-dependent agonist) produced vasodilation in control mice, but no response or vasoconstriction in R+A+ mice. In contrast, dilation of the basilar artery in response to a NO donor (NONOate) was similar in R+A+ mice and controls. Thus, Ang II produces potent constriction of cerebral arteries via activation of AT1A receptors and Rho-kinase. There are marked gender differences in cerebral vascular responses to Ang II. Endothelial function is greatly impaired in a genetic model of Ang II-dependent hypertension via a mechanism that involves superoxide.
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PMID:Cerebral vascular effects of angiotensin II: new insights from genetic models. 1609 17

The Rho/Rho kinase (ROCK) pathway is implicated in experimental hypertension. We, therefore, explored the role of ROCK2 genetic variation in human blood pressure (BP) regulation, exploiting the advantages of a human twin sample to probe heritability. The focus of this work is the common nonsynonymous variant at ROCK2: Thr431Asn. Cardiovascular and autonomic traits displayed substantial heritability (from approximately 33% to 71%; P<0.05). The Asn/Asn genotype (compared with Asn/Thr or Thr/Thr) was associated with greater resting systolic (P<0.001), diastolic (P<0.0001), and mean BP (P<0.0001); allelic variation at ROCK2 accounted for up to approximately 5% of BP variation (P<0.0001). Systemic vascular resistance was higher in Asn/Asn individuals (P=0.049), whereas cardiac output, large artery compliance, and vasoactive hormone secretion were not different. Coupling of the renin-angiotensin system to systemic resistance and BP was diminished in Asn/Asn homozygotes, suggesting genetic pleiotropy of Thr431Asn, confirmed by bivariate genetic analyses. The Asn/Asn genotype also predicted higher BP after environmental (cold) stress. The rise in heart rate after cold was less pronounced in Asn/Asn individuals, consistent with intact baroreceptor function, and baroreceptor slope was not influenced by genotype. Common genetic variation (Thr431Asn) at ROCK2 predicts increased BP, systemic vascular resistance (although not large artery compliance), and resistance in response to the endogenous renin-angiotensin system, indicating a resistance vessel-based effect on elevated BP. The results suggest that common variation in ROCK2 exerts systemic resistance-mediated changes in BP, documenting a novel mechanism for human circulatory control, and suggesting new possibilities for diagnostic profiling and treatment of subjects at risk of developing hypertension.
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PMID:Rho kinase polymorphism influences blood pressure and systemic vascular resistance in human twins: role of heredity. 1658 8

Although much is known about environmental factors that predispose individuals to hypertension and cardiovascular disease, little information is available regarding the genetic and signaling events involved. Indeed, few genes associated with the progression of these pathologies have been discovered despite intensive research in animal models and human populations. Here we identify Vav3, a GDP-GTP exchange factor that stimulates Rho and Rac GTPases, as an essential factor regulating the homeostasis of the cardiovascular system. Vav3-deficient mice exhibited tachycardia, systemic arterial hypertension and extensive cardiovascular remodeling. These mice also showed hyperactivity of sympathetic neurons from the time of birth. The high catecholamine levels associated with this condition led to the activation of the renin-angiotensin system, increased levels of kidney-related hormones and the progressive loss of cardiovascular and renal homeostasis. Pharmacological studies with drugs targeting sympathetic and renin-angiotensin responses confirmed the causative role and hierarchy of these events in the development of the Vav3-null mouse phenotype. These observations uncover the crucial role of Vav3 in the regulation of the sympathetic nervous system (SNS) and cardiovascular physiology, and reveal a signaling pathway that could be involved in the pathophysiology of human disease states involving tachycardia and sympathetic hyperactivity with unknown etiologies.
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PMID:Vav3 proto-oncogene deficiency leads to sympathetic hyperactivity and cardiovascular dysfunction. 1676 97

Estrogen protects against increases in arterial pressure (AP) by acting on blood vessels and on cardiovascular centers in the brain. The mechanisms underlying the effects of estrogen in the brain stem, however, are not clear. The aim of the present study was to determine whether ovariectomy affects AP via the Rho/Rho-kinase pathway in the brain stem. We performed bilateral ovariectomy in 12-week-old female spontaneously hypertensive rats. AP and heart rate (HR), measured using radiotelemetry in awake rats, were increased in ovariectomized rats compared with control rats (mean AP: 163+/-3 versus 144+/-4 mm Hg; HR: 455+/-4 versus 380+/-6 bpm). Continuous intracisternal infusion of Y-27632 significantly attenuated the ovariectomy-induced increase in AP and HR (mean AP: 137+/-6 versus 163+/-3 mm Hg; HR: 379+/-10 versus 455+/-4 bpm). In addition, we confirmed the increase of Rho-kinase activity in the brain stem in ovariectomized rats, and the increase was attenuated by intracisternal infusion of Y-27632 via the phosphorylated ezrin, radixin, and moesin (ERM) family, which are Rho-kinase target proteins. Furthermore, angiotensin II type 1 receptor expression in the brain stem was significantly greater in ovariectomized rats than in control rats, and the increase was partially reduced by intracisternal infusion of Y-27632. In a separate group of animals, we confirmed that the serum and cerebrospinal fluid 17beta-estradiol concentrations decreased in ovariectomized rats. These results suggest that depletion of endogenous estrogen by ovariectomy, at least in part, induces hypertension in female spontaneously hypertensive rats via activation of the renin-angiotensin system and the Rho/Rho-kinase pathway in the brain stem.
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PMID:Ovariectomy augments hypertension through rho-kinase activation in the brain stem in female spontaneously hypertensive rats. 1694 Feb 29


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