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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin-converting enzyme (ACE) inhibitors have played a highly beneficial role in the therapy of hypertension and congestive heart failure. Detailed analysis of some of the heart failure trials in patients with these diseases has uncovered unexpected benefits in the prevention of cardiovascular events. Paralleling these observations are the rapidly accruing basic studies describing important molecular and cellular effects of these agents. For example, ACE inhibition will prevent stimulation of smooth muscle cell angiotensin II receptors, thereby blocking both contractile and proliferative actions. In addition, ACE inhibition of kininase II inhibits the breakdown of bradykinin. Bradykinin is a direct stimulant of nitric oxide release from the intact endothelial cell. Thus, at the cellular level ACE inhibition shifts the balance of ongoing mechanisms in favor of those promoting vasodilatory, antiaggregatory, antithrombotic, and antiproliferative effects. These effects underlie the potential benefits of ACE inhibition in the therapy of coronary artery disease and atherosclerosis.
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PMID:Emerging concepts: angiotensin-converting enzyme inhibition in coronary artery disease. 911 53

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

Epidemiological evidence and estrogen replacement studies suggest that estrogen has a protective effect on the cardiovascular system against coronary artery disease. Vascular smooth muscle (VSM) cell replication has been shown to play a causative role in the pathogenesis of atherosclerosis. Therefore, in this study, we investigated the effect of chronic treatment of cultured guinea pig coronary artery VSM cells with physiological concentrations of 17beta-estradiol (E2) on thymidine incorporation, cell proliferation, and bradykinin-stimulated cytosolic calcium concentration ([Ca2+]i). Bradykinin at physiological concentrations causes contraction of endothelium-denuded guinea pig coronary artery rings in a concentration-dependent manner. VSM cells were first treated with low doses of E2 (10 pg/ml) for 1-2 days followed by treatment for 4-6 days with 50 pg/ml of E2, a concentration similar to that found in pregnancy. Using these protocols, we consistently observed the presence of E2-receptor mRNA in VSM cells by a ribonuclease protection assay. Fetal calf serum-stimulated [3H]thymidine incorporation was significantly reduced (P < 0.05) in E2-treated cells compared with untreated control cells. Similarly, E2 treatment significantly inhibited fetal calf serum-stimulated VSM cell proliferation compared with untreated control cells (P < 0.05). We also tested the hypothesis that E2 treatment attenuates agonist-stimulated [Ca2+]i in VSM cells because acute E2 treatment has been shown to produce relaxation of precontracted isolated coronary artery preparations. E2 treatment of VSM cells resulted in a significant decrease in bradykinin-stimulated [Ca2+]i compared with untreated cells (P < 0.05). In conclusion, our data demonstrate that estrogen at physiological concentrations directly regulates coronary VSM cell function.
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PMID:Estrogen reduces proliferation and agonist-induced calcium increase in coronary artery smooth muscle cells. 913 88

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

Hyperhomocyst(e)inemia, characterized by accelerated atherosclerosis, is believed to induce endothelial cell injury and promote atherothrombosis by supporting the generation of hydrogen peroxide. Earlier observations in our laboratory demonstrated that in vitro nitrosation of homocyst(e)ine (HCY) prevents the generation of hydrogen peroxide. We, therefore, hypothesized that stimulating the production of nitric oxide (NO) by endothelial cells would detoxify HCY by forming the corresponding S-nitrosothiol, S-nitroso-homocysteine. In an attempt to prove this hypothesis, media containing 1 mM L-arginine, 1 microM bradykinin, a known NO agonist, and one of the biologically relevant thiols (HCY, cysteine, or glutathione) at concentrations of 0, 0.05, 0.5 and 5.0 mM were incubated with bovine aortic endothelial cells (BAEC) for 0.5, 1 and 4 h. S-nitrosothiol (RSNO) concentrations were measured by photolysis-chemiluminescence. Nitric oxide synthase (eNOS or isoform 3) activity and Nos 3 steady-state mRNA levels were determined by the conversion of [3H]L-arginine to [3H]L-citrulline and Northern analysis, respectively. Results demonstrate that increasing concentrations of HCY, and not cysteine or glutathione, in the presence of bradykinin at 0.5, 1, and 4 h led to significant (P < 0.05 by ANOVA) time- and dose-dependent increases in RSNO produced by BAEC. Cells exposed to 1 microM calcium ionophore A23187 in the presence of 5.0 mM HCY also produced a time-dependent increase in RSNO compared to control (P < 0.05 by ANOVA). In an attempt to determine if de novo synthesis was occurring, BAEC were treated with bradykinin following a 4 h pretreatment with HCY. Pretreatment with HCY followed by stimulation also led to a time- and dose-dependent increase in RSNO production (P < 0.05 by ANOVA). Using high performance liquid chromatography with electrochemical detection, S-nitroso-homocysteine was identified following treatment of BAEC with HCY and bradykinin. The increase in RSNO production in the presence of bradykinin and HCY at 4 h occurred concomitantly with a 78% increase in eNOS activity and a 58% increase in steady-state Nos 3 mRNA, with no change in Nos 3 mRNA half-life, compared to control. A partial explanation for HCY's unique ability to support an increase in NO production was demonstrated by showing that the t1/2 of HCY in media was greater than that of cysteine or glutathione. These data show that, in the presence of an NO agonist, HCY increases RSNO production in a time- and dose-dependent fashion that is reflected by an increase in eNOS activity and Nos 3 transcription. These results suggest that stimulation of endogenous NO, or provision of an exogenous NO donor, may ameliorate endothelial cell injury and thereby decrease the atherothrombotic risk of hyperhomocyst(e)inemic states.
Atherosclerosis 1997 Jul 25
PMID:Stimulation of endothelial nitric oxide production by homocyst(e)ine. 924 63

Chymase shows a catalytic efficiency in the formation of angiotensin (Ang) II. In the present study, the characterization and primary structure of monkey chymase were determined, and the pathophysiological role of chymase was investigated on the atherosclerotic monkey aorta. Monkey chymase was purified from cheek pouch vascular tissue using heparin affinity and gel filtration columns. The enzyme rapidly converted Ang I to Ang II (Km = 98 microM, k(cat) = 6203/min) but did not degrade several peptide hormones such as Ang II, substance P, vasoactive intestinal peptide and bradykinin. The primary structure, which was deduced from monkey chymase cDNA, showed a high homology to that of human chymase (98%). The mRNA levels of the aorta chymase were significantly increased in the atherosclerotic aorta of monkeys fed a high-cholesterol diet. These results indicate that monkey chymase has a highly specific Ang II-forming activity and may be related to the pathogenesis of atherosclerosis.
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PMID:Induction of chymase that forms angiotensin II in the monkey atherosclerotic aorta. 925 95

The ACE/angiotensin II/bradykinin system is inextricably linked to some of the processes that contribute to the generation of atherosclerosis at genetic, molecular, biochemical and pharmacological levels. There is a large body of laboratory-derived experimental data that suggests that inhibition of ACE activity has antiproliferative, anti-inflammatory and vasodilatory effects that can modulate this atherosclerotic process from the earliest form of endothelial dysfunction, to delay of lesion formation in primary atherosclerosis or in myointimal proliferation after PTCA. The clinical evidence for these potential benefits is so far sparse. There are several possible explanations for these discrepancies. Firstly, the role of the ACE/bradykinin/angiotensin II system in the local vascular response to either the primary process of atherosclerosis, or to the injury induced by balloon angioplasty is likely to vary between species and models. Secondly, there is a tendency to ensure the presence of ACE inhibitor in high concentration before or during the vascular insult in animal models, whereas this has not been the case in the clinical studies of post-PTCA restenosis. Whilst the animal studies therefore offer potentially valuable insights into the mechanics of local vascular response, the ability of ACE inhibitors to interfere with such mechanisms now needs to be tested in clinical trials that are each aimed at precisely answering specific questions. The experimental data so far lend considerable support to the fact that drugs acting solely by interference with the angiotensin II-receptor complex are at a theoretical disadvantage, when compared with ACE inhibitors, since the former would be expected to have little effect on bradykinin-mediated activities. To the established benefits of ACE inhibitors in left ventricular dysfunction, and the interesting possibility that there may be an anti-ischaemic action in these circumstances, we may add the promise of the TREND study. In the coming years, there is an urgent requirement for intensive investigation into the ability of ACE inhibitors to modulate the various stages of the atherosclerotic spectrum. For now though, the jury remains out.
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PMID:Do ACE inhibitors modulate atherosclerosis? 934 63

An increasing body of evidence indicates that the endothelium is crucially involved in the regulation of coronary blood flow and cardiac function. Injury to the endothelium precipitates atherosclerosis by leading to smooth-muscle-cell migration and proliferation, induction of expression of growth factors and impairment in the plasmatic coagulation and endogenous fibrinolysis system. Strategically located between the circulating blood and the vascular smooth muscle, endothelial cells release numerous vasoactive substances regulating the function of vascular smooth muscle and trafficking blood cells. Important endothelium-derived vasodilators are prostacyclin, bradykinin, nitric oxide and, independent of the former, endothelium-derived hyperpolarizing factor. In particular, nitric oxide inhibits cellular growth and migration. In concert with prostacyclin, nitric oxide exerts potent antiatherogenic and thromboresistant properties by preventing platelet aggregation and cell adhesion. These effects are counterbalanced by endothelial vasoconstrictors, such as angiotensin II and endothelin-1, both of which exert prothrombotic and growth-promoting properties. Modern therapeutic strategies in coronary artery disease focus on preserving or restoring endothelial integrity. Whereas nitrates partly substitute deficient endogenous nitric oxide, calcium antagonists counteract angiotensin II and endothelin-1 at the level of vascular smooth muscle by reducing Ca2+ inflow and facilitating the vasodilator effects of nitric oxide. Beyond inhibiting the renin-angiotensin system, angiotensin-converting enzyme inhibitors diminish the inactivation of bradykinin, thus leading to an augmentation of nitric oxide release. Furthermore, newly developed specific endothelin antagonists will provide us with greater insight into the beneficial effects of restoring endothelial dysfunction in cardiovascular disease. Thus, drugs can directly affect endothelial function, prevent the action of endothelial mediators, substitute for deficient endothelial factors or indirectly exert protective effects by interfering with cardiovascular risk factors.
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PMID:The endothelium in coronary artery disease. 939 88

The endothelium mediates a number of responses (relaxation or contraction) of arteries and veins from animals and humans. The endothelium-dependent relaxations are due to the release, by endothelial cells, of potent non-prostanoid vasodilator substances. Among these, the best characterized is endothelium-derived relaxing factor (EDRF), which is believed to be nitric oxide (NO). Nitric oxide is formed by the metabolism of L-arginine by the constitutive NO synthase of endothelial cells. In arterial smooth muscle, the relaxation evoked by EDRF is explained by the stimulation by NO of soluble guanylate cyclase that leads to the accumulation of cGMP. In a number of animal blood vessels and in human coronary arteries, the endothelial cells release a substance that causes hyperpolarization of the cell membrane (endothelium-derived hyperpolarizing factor, EDHF). The release of EDRF from the endothelium can be mediated by both pertussis toxin-sensitive (alpha 2-adrenoceptor activation, serotonin, aggregating platelets, leukotrienes) and insensitive (adenosine diphosphate (ADP), bradykinin) G proteins. In blood vessels from animals with regenerated and reperfused endothelium, and/or atherosclerosis, there is a selective loss of the pertussin toxin-sensitive mechanism of EDRF release, which favours the occurrence of vasospasm, thrombosis and cellular growth. The available information from isolated human blood vessels or obtained in situ concurs with the conclusions reached from studies with isolated animal tissues. In addition to relaxing factors, the endothelial cells can produce contracting factors (endothelium-derived contracting factors; EDCFs) which include superoxide anions, endoperoxides, thromboxane A2 and endothelin. From animal studies it can be concluded that the propensity to release EDCFs is maintained, or even augmented, in diseased blood vessels. The switch from a normally predominant release of EDRFs to that of EDCFs may play a crucial role in atherosclerosis.
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PMID:Endothelial dysfunction and atherosclerosis. 940 68

The ability of the vasculature to modify its geometry in accordance with conditions of its microenvironment--the process of vascular remodeling--is an important pathobiologic process common to vascular disorders such as atherosclerosis, restenosis after angioplasty, and hypertension. Vascular remodeling characterizes the natural history of atherosclerosis, contributes to increased vascular resistance, and may contribute to the clinical complications of hypertension. A growing body of evidence indicates that locally generated vasoactive substances such as angiotensin II and nitric oxide are important determinants of the natural history of vascular disease. In particular, angiotensin II may promote vascular lesion formation by increasing vascular cell population via increased cell growth and decreased programmed cell death, and it may also alter extracellular matrix composition. Thus, angiotensin II is a pleiotropic local mediator capable of modulating cell growth, programmed cell death, migration of vascular smooth muscle cells, and extracellular matrix modulation, all of which are biologic mechanisms of vascular remodeling and intimal formation. This is proposed to occur via a local tissue angiotensin system. Angiotensin II may also promote chronic hypertension by modulating the vascular redox state and promoting the catabolism of the endothelium-derived nitric oxide, an endogenous inhibitory vasodilator. Because angiotensin-converting enzyme (ACE) is strategically positioned to influence the activity of at least three local vasoactive systems--angiotensin II, nitric oxide, and bradykinin--blocking ACE with ACE inhibition may have profound effects on ventricular and vascular structure and function, and have particular efficacy in preventing the morbidity and mortality of vascular diseases such as hypertension and atherosclerosis.
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PMID:Vasculoprotective and cardioprotective mechanisms of angiotensin-converting enzyme inhibition: the homeostatic balance between angiotensin II and nitric oxide. 942 48


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