Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxynitrite is a potent oxidant formed endogenously by the near diffusion-limited reaction of nitric oxide with superoxide anion. Peroxynitrite specifically adds a nitro group to the ortho position of the phenolic ring of free and protein-associated tyrosines to form the stable product 3-nitro-L-tyrosine. Systemic administration of 3-nitro-L-tyrosine markedly inhibits the subsequent hemodynamic responses to alpha 1- and beta-adrenoceptor agonists in anesthetized rats. Angiotensin II is an important modulator of vascular tone. The vasoconstrictor effects of this hormone are known to involve the release of catecholamines from sympathetic tissues. In the present study, we examined whether 3-nitro-L-tyrosine (2.5 mumol/kg i.v.) would attenuate the hemodynamic responses produced by angiotensin II (0.1-1.0 microgram/kg i.v.). Angiotensin II produced increases in mean arterial pressure, and renal and mesenteric vascular resistances, but no changes in hindquarter vascular resistance. The pressor and renal and mesenteric vasoconstrictor responses produced by angiotensin II were significantly attenuated 30-60 min following the administration of 3-nitro-L-tyrosine. Further attenuation of these responses was evident 120-180 min following the administration of 3-nitro-L-tyrosine. The alpha 1-adrenoceptor antagonist prazosin also diminished the pressor and renal and mesenteric vasoconstrictor responses produced by angiotensin II. These results demonstrate that 3-nitro-L-tyrosine inhibits the hemodynamic responses to angiotensin II, possibly through the inhibition of alpha 1-adrenoceptor-mediated events. The effect of 3-nitro-L-tyrosine on the hemodynamic action of angiotensin II raises the possibility that 3-nitro-L-tyrosine may be involved in the pathogenesis of the hemodynamic disturbances associated with inflammatory conditions, such as atherosclerosis, ischemia-reperfusion, and sepsis, where formation of peroxynitrite is favored.
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PMID:The peroxynitrite product 3-nitro-L-tyrosine attenuates the hemodynamic responses to angiotensin II in vivo. 896 Aug 80

Angiotensin II (AII) plays a crucial role in controlling the proliferation and migration of vascular smooth muscle cells (VSMCs). The present study was undertaken to determine if troglitazone (Tro) has an effect on the G-protein coupled signaling through AII type I (AT-1) receptors in cultured rat aortic VSMCs. AII-induced MAP kinase activation was inhibited 67.9% by Tro. AII-induced DNA synthesis and migration was completely inhibited by Tro or by the AT-1 receptor blocker irbesartan. The present study demonstrates that troglitazone inhibits AII-induced DNA synthesis, migration and MAP kinase activation in VSMCs which are important molecular events for the development of neointimal hyperplasia and atherosclerosis.
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PMID:Troglitazone inhibits angiotensin II-induced DNA synthesis and migration in vascular smooth muscle cells. 900 May 25

Angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) are major components of the renin-angiotensin systems. An association between myocardial infarction (MI) and the ACE DD genotype of the insertion/deletion (ID) polymorphism in intron 16 of the ACE gene has been reported. However, other similarly designed studies have not found such an association. Angiotensin II, the product of AGT, has a direct effect on vascular tone; and a variant in the AGT gene has been found to be associated with MI in the Japanese. This case-control study was initiated to investigate whether the ACEI/D and AGT M235T polymorphisms are associated with an increased risk for coronary heart disease (CHD) and MI. Our study groups were composed of participants in the National Heart Lung Blood Institute (NHLBI) Family Heart Study (FHS) selected from three population-based studies: two Atherosclerosis Risk in Communities (ARIC) centers (Forsyth County, NC, and Minneapolis, MN), and the Framingham Heart Study. In multivariate analysis within ARIC Caucasians, a significant positive association was found between CHD (controls = 230, cases = 232) and the AGT TT genotype (P = 0.022; OR = 1.84, 1.09-3.10 95% CI). When we restricted the analysis to a low-risk group for CHD (controls = 70, cases = 35) an interaction between the ACE DD and AGT TT genotypes was significant (P = 0.025; OR = 5.02 1.22-20.6 95% CI). After further subsetting low-risk cases to those with a definite MI (controls = 74, cases = 16), we found that the associations with the ACE DD genotype was also significant (P = 0.013, OR = 3.94, 1.28-12.2 95% CI). Comparable tests in the Framingham sample failed to support an association of these markers with CHD. In conclusion, within selected groups the ACE D and AGT 235T alleles are statistically associated with CHD and MI, and there is a synergistic interaction between the two alleles. These results and those from previous studies together suggest that the association of these two loci is neither strong nor consistent and involves a complex interaction among risk factors and genotypes.
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PMID:Associations between candidate loci angiotensin-converting enzyme and angiotensinogen with coronary heart disease and myocardial infarction: the NHLBI Family Heart Study. 903 1

Growth arrest-specific homeobox (Gax) gene was isolated from rat aorta cDNA library and its expression was largely confined to the cardiovascular tissues. Gax gene was rapidly downregulated by platelet-derived growth factor in vascular smooth muscle cells (VSMCs) and overexpressed Gax was reported to reduce the neointimal thickening after balloon injury in vivo. We have demonstrated that angiotensin II (Ang II) stimulates vascular growth. In contrast, we also reported that C-type natriuretic peptide (CNP) is secreted from vascular endothelial cells to act as a novel endothelium-derived relaxing peptide and inhibits vascular growth via cGMP cascade. In the present study, we examined the effects of Ang II and CNP on Gax gene expression in VSMCs. In quiescent rat aortic VSMCs. Gax mRNA (2 3 kb) level became negligible 6 hours after the addition of Ang II (10(-6) mol/L). The inhibitory action of Ang II on Gax mRNA expression (ED50: 10(-11) mol/L) was almost completely blocked by an AT1R antagonist, CV11974. In contrast, CNP 10(-6) mol/L augmented Gax mRNA expression to exhibit 1.8-fold increase of the control 12 hours after the stimulation. This effect of CNP was mimicked by the addition of 8-bromoadenosine 3'-5'-cyclic monophosphate. The addition of C-ANF[4-23], an atrial natriuretic peptide-C receptor-specific agonist and devoid of stimulating cGMP production, exhibited no effect on Gax mRNA expression. Simultaneous administration of Ang II and CNP revealed that CNP (10(-6) mol/L) significantly attenuated the inhibitory action of Ang II (10(-10) mol/L) on Gax mRNA expression. These results suggest that Gax is a common transcription factor involved in the signaling pathway of vascular growth for Ang II and CNP and regulates the cell cycle and/or phenotype of VSMCs for vascular remodeling in hypertension and atherosclerosis.
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PMID:Opposite regulation of Gax homeobox expression by angiotensin II and C-type natriuretic peptide. 903 31

The aim of the present study is primarily to re-examine an animal model of acute myocardial infarction (AMI) and arterial thrombosis, developed by Constantinides and his colleagues in the 1960s, in both heritable hyperlipidemic rabbits and normal rabbits because they did not study these rabbits. The groups in this study consisted of 29 normal rabbits and 29 Watanabe heritable hyperlipidemic (WHHL) rabbits. These rabbits were administered Russell's viper venom (RVV) as a procoagulant, intraperitoneally with serotonin or angiotensin II or saline, intravenously. As a control, 10 normal and 17 WHHL rabbits were administered intravenously with either angiotensin II or saline. These treatments were given on 2 successive days. AMI lesion was found in 8 of 29 normal and 7 of 29 WHHL rabbits receiving RVV and angiotensin or serotonin. Angiotensin II promoted the incidence of aortic thrombosis associated with segmental medial necrosis and an intimal disruption in WHHL rabbits receiving RVV. In the normal rabbits, angiotensin II in addition to RVV induced segmental medial necrosis of the aorta, but angiotensin II alone did not. Thus, we postulated that a synergistic effect of RVV as a cytotoxic substance and a sudden increase in the aortic wall tension by angiotensin II might thus result in acute aortic medial necrosis. The conclusion was that no close correlation between coronary arteriosclerosis and AMI was found in this animal model. The intravenous administration of angiotensin promoted aortic medial necrosis even in normal rabbits treated with RVV and then accelerated aortic thrombosis in the WHHL rabbits treated with RVV.
Atherosclerosis 1997 Feb 10
PMID:Aortic medial necrosis with or without thrombosis in rabbits treated with Russell's viper venom and angiotensin II. 905 Jul 71

Many reports have shown inhibitory effects of angiotensin-converting enzyme (ACE) inhibitors on the progression of atherosclerotic plaque lesions in vascular tissue of experimental models. However, no report has shown alterations of ACE activity in vascular tissue during the process of atherosclerosis. We measured ACE activity in plasma and aortic tissue in rabbits fed a cholesterol-rich (1%) or normal diet for 10 weeks. We also evaluated the blood pressure response to angiotensin (Ang) I and II. These data were compared in untreated rabbits and in rabbits receiving chronic treatment with an ACE inhibitor, enalapril (3 mg/kg/day for 10 weeks). ACE activity in aortic tissue, but not in plasma, in cholesterol-fed rabbits was gradually but significantly increased compared with that in noncholesterol-fed rabbits even after the 4-week feeding period, when no atherosclerotic lesion was observed in the aortic tissue. Treatment with enalapril for 10 weeks, but not 4 weeks, significantly reduced the ACE activity in aortic tissue in association with the reductions in the elevated Ang II level and the atherosclerotic plaque area of the aortic tissue. These results indicated that ACE activity in aortic tissue was increased during the early phase of atherosclerotic process.
Atherosclerosis 1997 Apr
PMID:Vascular angiotensin-converting enzyme activity in cholesterol-fed rabbits: effects of enalapril. 912 48

New evidence suggests an interaction between hyperlipidemia, activation of the renin-angiotensin system, and atherosclerotic disease. In patients with atherosclerosis and hyperlipidemia, coronary endothelial dysfunction is usually diffuse and affects vasomotor tone, platelet activity, thrombosis, fibrinolysis, and regulation of inflammatory cells. Angiotensin II, an important oxidant, alters the binding of low-density-lipoprotein (LDL) cholesterol to its receptors and increases endothelial uptake of LDL. Endothelial dysfunction is worsened by the suppression of nitric oxide production and/or release via angiotensin II-associated degradation of bradykinin and oxygen free radical production, resulting in inadequate vasorelaxation. Therapy with angiotensin-converting enzyme (ACE) inhibitors appears to eliminate these untoward effects and may ameliorate the tendency for myocardial infarction associated with elevated plasma levels of angiotensin II. Although the role of ACE inhibitors in the prevention and/or treatment of coronary artery disease in patients without left ventricular dysfunction remains to be established, the capacity of ACE inhibition to correct endothelial dysfunction offers promise. The ability of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors to improve endothelial function, prevent the progression of coronary atherosclerosis, reduce the incidence of ischemic events, and improve survival is well known. Potentially, ACE inhibitors may have an additive or synergistic effect on the development of atherosclerosis and the clinical consequences of this disease when used in combination therapy with lipid-lowering strategies.
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PMID:The potential use of angiotensin-converting enzyme inhibitors in patients with hyperlipidemia. 912 18

In this review, the role of tyrosine kinases in angiotensin II-mediated signal transduction pathways in vascular smooth muscle is discussed. Angiotensin II was isolated by virtue of its vasoconstrictor abilities and has long been thought to play a critical role in hypertension. However, recent studies indicate important roles for angiotensin II in inflammation, atherosclerosis, and congestive heart failure. The expanding role of angiotensin II indicates that multiple signal transduction pathways are likely to be activated in a tissue-specific manner. Exciting recent data show that angiotensin II directly stimulates tyrosine kinases, including pp60(c-src) kinase (c-Src), focal adhesion kinase (FAK), and Janus kinases (JAK2 and TYK2). Angiotensin II may activate receptor tyrosine kinases, such as Axl and platelet-derived growth factor, by as-yet-undefined autocrine mechanisms. Finally, unknown tyrosine kinases may mediate tyrosine phosphorylation of Shc, Raf, and phospholipase C-gamma after angiotensin II stimulation. These angiotensin II-regulated tyrosine kinases appear to be required for angiotensin II effects, such as vasoconstriction, proto-oncogene expression, and protein synthesis, on the basis of studies with tyrosine kinase inhibitors. Thus, understanding angiotensin II-stimulated signaling events, especially those related to tyrosine kinase activity, may form the basis for the development of new therapies for cardiovascular diseases.
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PMID:Angiotensin II signal transduction in vascular smooth muscle: role of tyrosine kinases. 913 Apr 41

Thrombin has been implicated as an important mediator of vascular lesion formation in atherosclerosis and restenosis. To investigate a potential role for thrombin signaling in the vascular response to hypertension, we have studied thrombin receptor (TR) expression and regulation in hypertensive rats. Aortic TR mRNA was upregulated by angiotensin II (Ang II)-induced hypertension (10.7 +/- 2.5 times control, P < .02), which correlated with a 4-fold increase in thrombin-induced constriction in isolated endothelium-denuded aortic rings. The AT1 receptor antagonist losartan normalized blood pressure and TR mRNA. Conversely, lowering blood pressure to the same degree with hydralazine did not abolish the upregulation of TR mRNA expression. When low-renin low-Ang II hypertension was induced in Dahl salt-sensitive rats, there was no detectable increase in the expression of aortic thrombin receptor mRNA. Finally, treatment with a chimeric heparin-binding form of the recombinant human Cu/Zn superoxide dismutase caused complete inhibition of TR mRNA upregulation, suggesting that an increased rate of superoxide anion production is an important signaling mechanism. Thus, increased TR expression via a redox-sensitive mechanism in the aortic smooth muscle of rats treated with Ang II represents a novel in vivo mechanism through which the hypertensive effects of Ang II are mediated.
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PMID:Vascular thrombin receptor regulation in hypertensive rats. 916 86

Atherosclerosis and its consequences account for most of the morbidity and mortality in Western countries. It is a disease of the intima and primarily involves four cell types, i.e., endothelial and vascular smooth muscle cells, monocytes and platelets. In recent years, knowledge on the cellular and molecular mechanisms of these cells and their alterations by cardiovascular risk factors and in atherosclerosis has greatly expanded. In particular, it has become clear that endothelial cells play a crucial role in the regulation of platelet function, coagulation, and vascular tone and structure. Interestingly, endothelial dysfunction occurs early, particularly if cardiovascular risk factors such as hyperlipidemia, hypertension and diabetes are present. This could lead to adhesion of circulating platelets and monocytes and increased accumulation of lipids in the intima, as well as increased contraction, migration and proliferation of vascular smooth muscle cells. One of the enzymes with a key role in vascular homeostasis is angiotensin I converting enzyme (ACE). ACE is located on the endothelial cell membrane and is responsible for the conversion of angiotensin I into angiotensin II, as well as for the breakdown of bradykinin. While the antihypertensive effect of ACE inhibitors probably contributes to their antiatherogenic effects, other mechanisms are likely to be of greater importance. These direct antiatherogenic effects attributable to ACE inhibition are related to their vasculoprotective properties, including antiproliferative and antimitogenic activity, effects on endothelial function, protection against plaque rupture, antithrombotic effects, and possible antioxidant properties. There is overwhelming evidence to demonstrate the beneficial effects of long-term ACE inhibitor treatment in heart failure, acutely for suspected myocardial infarction (MI), and following MI in patients with left ventricular dysfunction. Hypercholesterolemia is a health risk, and epidemiological studies have shown a line between total cholesterol levels and the risk of cardiac events. Studies have shown that lowering the levels of total and low-density lipoprotein cholesterol using HMG-CoA reductase inhibitors can result in a decrease in cardiac morbidity and mortality. Angiographic studies of coronary arteries have demonstrated a disparity between the decrease in cardiac events and the extent of regression of coronary artery lesions. Mechanisms other than the regression of coronary stenosis may therefore be important in the beneficial effect of cholesterol lowering. It may be of major importance that lipid-lowering therapy is associated with improved endothelial function and decreased platelet activity. Thus, both ACE inhibitors and HMG-CoA reductase inhibitors have vasculoprotective properties which may explain their beneficial effects on cardiovascular morbidity and mortality.
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PMID:[Pharmacotherapy of arteriosclerosis and its complications. Effect of ACE inhibitors and HMG-CoA-reductase inhibitors]. 919 90


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