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)

Asymmetric dimethylarginine (ADMA) is synthesized during the methylation of protein arginine residues by protein arginine methyltransferases (PRMT) and is released during proteolysis. ADMA is a competitive inhibitor of nitric oxide synthase and may decrease NO availability. ADMA is eliminated by renal excretion or is metabolized by dimethylarginine dimethylaminohydrolase (DDAH) to citruline and dimethylamine. Two other endogenous methylarginines are also synthesized by PRMT: N-monomethyl-L-arginine (L-NMMA) and symmetric dimethylarginine (SDMA). L-NMMA inhibits NO synthase but its concentrations in circulation are much lower than ADMA whereas SDMA is inactive. Plasma concentration of ADMA is markedly increased in patients with chronic renal failure and moderately increased in patients with many other diseases including hyperlipidemia, diabetes mellitus, arterial hypertension, hyperhomocysteinemia and heart failure. The increased concentration of ADMA is positively correlated with markers of atherosclerosis, such as carotid artery intima-media thickness and has a predictive value for acute cardiovascular events in prospective studies. Angiotensin-converting enzyme inhibitors, angiotensin AT1 receptor antagonists, vitamin E and, according to some studies, estrogens used in hormonal replacement therapy reduce plasma ADMA concentration, which may contribute to their beneficial effect on NO synthesis and endothelial function. However, in some states associated with excess of NO, such as septic shock or excitotoxic neuronal injury ADMA may be protective by limiting toxic effect of high concentrations of NO. This article reviews the effect of pharmacotherapy on ADMA metabolism and its possible clinical implications.
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PMID:Asymmetric dimethylarginine (ADMA) as a target for pharmacotherapy. 1670 18

The endothelium is critically involved in modulating vascular tone through the release of vasodilator (mainly nitric oxide; NO) and vasoconstrictor agents. Under normal conditions the endothelium induces NO-mediated vasodilation, and opposes cell adhesion and thrombosis. Angiotensin II-induced generation of reactive oxygen species plays a key role in the pathophysiology of endothelial dysfunction by reducing NO bioavailability. Endothelial dysfunction is associated with several pathologic conditions, including hypertension and diabetes, and is characterized by altered vascular tone, inflammation, and thrombosis in the vascular wall. Inhibition of the renin-angiotensin-aldosterone system has induced beneficial effects on endothelial function in animals and humans. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists have improved endothelial function in hypertension and diabetes, slowed the progression of atherosclerosis, and reduced the risk associated with cardiovascular disease.
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PMID:Inhibition of the renin angiotensin system: implications for the endothelium. 1687 78

Patients with peripheral vascular disease are less likely to receive optimal medical management than patients with coronary artery disease. However, early medical treatment is critical because it is profoundly beneficial and the benefits are maximized. Even in patients with advanced disease requiring invasive intervention, medical management has been proven to improve outcome, prolong the success of the intervention, improve functional capacity, and prolong life. The vascular surgeon should be knowledgeable enough to initiate basic medical therapy and to define for their patients the goals that need to be met to optimize their medical management. The vascular surgeon should be instrumental in assuring that the peripheral vascular patient receives medical therapy of the same standard as the patient with coronary disease. The major modifiable risk factors in the vascular patient are: smoking, high blood pressure, hyperlipidemia, physical inactivity, obesity, and diabetes. In addition, the use of beta blockers for patients with coronary disease and antiplatelet therapy as well as angiotensin-converting enzyme (ACE) inhibitors are recommended for all patients with peripheral vascular disease. Statins have favorable effects on multiple interrelated aspects of vascular biology important in atherosclerosis. In particular they have beneficial effects on inflammation, plaque stabilization, endothelial dysfunction, and thrombosis. Statins have also been shown to be beneficial in acute vascular events. Angiotensin-converting enzyme inhibitors have been shown to reduce cardiovascular morbidity and mortality in patients with peripheral arterial disease regardless of the presence or absence of hypertension. A number of the pleiotropic effects of statins are shared by ACE inhibitors. In summary, patients with known vascular disease should be treated aggressively with a combination of a HMG CoA reductase inhibitor, an angiotensin-converting enzyme inhibitor, an antiplatelet agent and a beta blocker if there is a history of coronary disease. They should also receive tight control of their blood pressure and blood sugar. Smokers should be encouraged to stop smoking and should be provided with pharmaceutical and emotional support by their physicians. All of these patients should have their body mass index as close to normal as possible and be on a therapeutic lifestyle diet. Regular aerobic exercise is also indicated. Patients with symptomatic claudication should be considered for cilostazol. Patients with multiple risk factors for vascular disease, but who do not have documented disease should also be on statin therapy. As more studies define the linear relationship between lower LDL-C levels and lowered risk of vascular events, indicating that the lower the LDL-C level, the lower the risk, experts are advocating more aggressive lipid-lowering therapy. In patients with peripheral arterial disease, some experts now advocate lowering the goal of LDL therapy to 70 mg/dL.
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PMID:Optimal medical management of peripheral arterial disease. 1727 51

There have been many reports regarding the association between renin-angiotensin system (RAS) gene polymorphisms and coronary artery disease (CAD) or acute myocardial infarction (AMI), but the results are inconsistent. In the present study, we used several new approaches with multilocus data to reappraise this issue in a large and relatively homogeneous Taiwanese population. A total of 1254 consecutive patients who underwent cardiac catheterization (735 with documented coronary artery disease and 519 without) between 1996 and 2003 were recruited. Angiotensin-converting enzyme gene insertion/deletion (I/D) polymorphism; T174M, M235T, G-6A, A-20C, G-152A and G-217A polymorphisms of the angiotensinogen gene; and A1166C polymorphism of the angiotensin II type I receptor gene were genotyped. In single-locus analyses, no locus was associated with CAD, history of AMI and three-vessel CAD, either with or without adjustment for conventional CAD risk factors. For multilocus analyses, we recreated a balanced population, with the controls individually matched to the cases regarding the conventional CAD risk factors. We found that the angiotensinogen gene haplotype profile was significantly different between the cases and controls (chi2=31.6, P=0.030) in haplotype analyses. Furthermore, significant three-locus (G-217A, M235T and I/D) gene-gene interactions were detected by multifactor-dimensionality reduction method (highest cross-validation consistency 10.0, lowest prediction error 40.56%, P=0.017) and many even higher order gene-gene interactions by multilocus genotype disequilibrium tests (16 genotype disequilibria exclusively found in the controls, all of which included at least two genes among AGT, ACE and AT1R genes). Our study is the first to demonstrate epistatic, high-order, gene-gene interactions between RAS gene polymorphisms and CAD. These results are compatible with the concept of multilocus and multi-gene effects in complex diseases that would be missed with conventional approaches.
Atherosclerosis 2007 Nov
PMID:Renin-angiotensin system gene polymorphisms and coronary artery disease in a large angiographic cohort: detection of high order gene-gene interaction. 1711 72

Impaired fibrinolytic function, characterized by increased plasminogen activator inhibitor type 1 (PAI-1) levels and decreased tissue plasminogen activator (t-PA) activity, has been found in patients with hypertension and may account in part for the increased risk of atherosclerosis and its clinical complications in these patients. Failure to correct this prothrombotic state may be one of the possible reasons for the disappointing effect of antihypertensive treatment on the incidence of coronary events. In this regard, data from the literature indicate that different antihypertensive drugs may vary in their influence on fibrinolysis. Scarce and conflicting data exist regarding the effects of diuretics and beta-blockers on the fibrinolytic system. Angiotensin-converting enzyme (ACE) inhibitors (ACE-I) have generally been shown to improve the fibrinolytic balance by reducing plasma PAI-1 levels, calcium channel blockers (CCB) have been reported to increase t-PA activity, and angiotensin receptor blockers (ARB) seem to be neutral in their effect. Interesting data have been reported about the positive impact on fibrinolysis of combining an ACE-I with a CCB, which resulted in a decrease of PAI-1 caused by ACE inhibition, and an increase in t-PA resulting from calcium channel blockade. The positive effect of ACE-I on the fibrinolytic system has been related to: 1) inhibition of angiotensin II, which stimulates PAI-1 expression; 2) inhibition of degradation of bradykinin, a potent stimulus for tPA production; and 3) improvement of insulin sensitivity. The mechanisms underlying the CCB effect on t-PA are less clear, but a direct action of CCB on vascular endothelium has been reported to play a major role. The greater improvement in the fibrinolytic balance because of the combined action of ACE inhibition and Ca antagonism represents a further indication to the use of combinations of ACE-I and CCB in the treatment of hypertension.
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PMID:Antihypertensive drugs and fibrinolytic function. 1716 77

Angiotensin-converting enzyme (ACE)2 is a recently identified homologue of ACE. As ACE2 inactivates the pro-atherogenic angiotensin II, we hypothesize that ACE2 may play a protective role in atherogenesis. The spatiotemporal localization of ACE2 mRNA and protein in human vasculature and a possible association with atherogenesis were investigated using molecular histology (in situ hybridization, immunohistochemistry). Also, the ACE : ACE2 balance was investigated using enzymatic assays. ACE2 mRNA was expressed in early and advanced human carotid atherosclerotic lesions. In addition, ACE2 protein was present in human veins, non-diseased mammary arteries and atherosclerotic carotid arteries and expressed in endothelial cells, smooth muscle cells and macrophages. Quantitative analysis of immunoreactivity showed that total vessel wall expression of ACE and ACE2 was similar during all stages of atherosclerosis. The observed ACE2 protein was enzymatically active and activity was lower in the stable advanced atherosclerotic lesions, compared to early and ruptured atherosclerotic lesions. These results suggest a differential regulation of ACE2 activity during the progression of atherosclerosis and suggest that this novel molecule of the renin-angiotensin system may play a role in the pathogenesis of atherosclerosis.
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PMID:Angiotensin-converting enzyme 2 (ACE2) expression and activity in human carotid atherosclerotic lesions. 1849 93

Cardiovascular (CV) risk factors, primarily arterial hypertension, modify the structural and functional features of the myocardium and the blood vessels, a process known as CV remodeling. Cardiac remodeling refers to changes in left ventricular (LV) geometry, such as concentric LV geometry and LV hypertrophy (LVH), an independent hallmark of CV risk. Vascular remodeling consists of structural changes of the arterial walls, such as increased intima-media thickness, arterial stiffening, and deteriorating endothelial function. CV remodeling is to a large extent a result of compensatory mechanisms, and its pathophysiology is partially mediated by the activation of the renin-angiotensin-aldosterone system and its primary effector peptide angiotensin II, which together play a key role in the progression of CV disease. Angiotensin-converting enzyme (ACE) inhibitors, a class of drugs used in the treatment of arterial hypertension, appear to be effective in controlling or even reversing CV remodeling, independently of simple blood pressure reduction. Evidence shows that ACE inhibitors counteract CV remodeling by reducing LV mass and regressing LVH, attenuating vascular atherosclerosis and improving vascular compliance. ACE inhibitors possessing a sulfhydryl moiety appear to have additional benefits in increasing nitric-oxide release and improving vascular endothelial function.
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PMID:Risk factor-induced cardiovascular remodeling and the effects of angiotensin-converting enzyme inhibitors. 1852 Sep 54

Stroke is one of the most complex diseases with several subtypes, arising from numerous gene-gene and gene-environmental interactions. The aim of our study was to investigate whether the insertion/deletion polymorphism in Angiotensin-converting enzyme gene is associated with ischemic stroke in a South Indian population. One hundred and sixty two patients and one hundred and fifty controls were studied for the presence of ACE gene polymorphism by PCR technique. The stroke patients were subtyped according to TOAST criteria, taking into account all the available data. There were significant differences in the genotypic distribution and allelic frequency between the patients and healthy controls. Furthermore the D allele was significantly associated with intracranial large artery atherosclerosis. However, the association was insignificant with other stroke subtypes. We observed that ACE ID/DD genotypes are associated with an elevated incidence of stroke in a South Indian population from Andhra Pradesh. Moreover, ACE gene polymorphism was found to contribute to the risk of developing intracranial large artery atherosclerosis, which is the most frequent subtype in this region.
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PMID:Angiotensin-converting enzyme insertion/deletion polymorphism and the risk of ischemic stroke in a South Indian population. 1858 76

Angiotensin-converting enzyme inhibitors proved to be effective in the primary and secondary prevention of cardiovascular diseases. Clinical effectiveness of this group of agents may largely depend on their pleiotropic effects. The purpose of this study was to compare the effects of plasma- and tissue-type angiotensin-converting enzyme inhibitors on blood pressure and on systemic inflammation, hemostasis and oxidative functions in normotensive patients with stable coronary artery disease. Ninety patients with stable coronary artery disease enrolled into the study were randomly divided into three different groups, simultaneously treated with enalapril (20 mg/d, n = 30), perindopril (4 mg/d, n = 30) or placebo (n = 30). Plasma lipid profile and the levels of oxidized low density lipoproteins (LDLs), monocyte chemoattractant protein (MCP)-1, interleukin-10, C-reactive protein (CRP), fibrinogen and plasminogen activator inhibitor (PAI)-1 were determined at the beginning of the study and after 30 and 90 days of treatment. Seventy-six patients completed the trial. Neither enalapril nor perindopril affected blood pressure or plasma lipids. Perindopril significantly reduced plasma levels of oxidized LDLs, CRP, MCP-1, fibrinogen and PAI-1, and increased interleukin-10. The effect of enalapril on these markers of systemic inflammation, hemostasis and oxidative functions was much less pronounced. The results showed that enalapril and perindopril were devoid of a blood pressure-lowering effect in normotensive patients with stable coronary artery disease. Perindopril was superior to enalapril in exhibiting antioxidant, antithrombotic and profibrinolytic activities. The treatment-induced changes in the balance between pro- and antiinflammatory cytokines and in hemostasis may contribute to the clinical effectiveness of tissue angiotensin-converting enzyme inhibitors in the therapy of atherosclerosis-related disorders.
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PMID:Pleiotropic effects of angiotensin-converting enzyme inhibitors in normotensive patients with coronary artery disease. 1879 20

Angiotensin-converting enzyme (ACE) and its homologue angiotensin-converting enzyme 2 (ACE2) are critical counter-regulatory enzymes of the renin-angiotensin system, and have been implicated in cardiac function, renal disease, diabetes, atherosclerosis and acute lung injury. Both ACE and ACE2 have catalytic activity that is chloride sensitive and is caused by the presence of the CL1 and CL2 chloride-binding sites in ACE and the CL1 site in ACE2. The chloride regulation of activity is also substrate dependent. Site-directed mutagenesis was employed to elucidate which of the CL1 and CL2 site residues are responsible for chloride sensitivity. The CL1 site residues Arg186, Trp279 and Arg489 of testicular ACE and the equivalent ACE2 residues Arg169, Trp271 and Lys481 were found to be critical to chloride sensitivity. Arg522 of testicular ACE was also confirmed to be vital to the chloride regulation mediated by the CL2 site. In addition, Arg514 of ACE2 was identified as a residue critical to substrate selectivity, with the R514Q mutant, relative to the wild-type, possessing a fourfold greater selectivity for the formation of the vasodilator angiotensin-(1-7) from the vasoconstrictor angiotensin II. The enhancement of angiotensin II cleavage by R514Q ACE2 was a result of a 2.5-fold increase in V(max) compared with the wild-type. Inhibition of ACE2 was also found to be chloride sensitive, as for testicular ACE, with residues Arg169 and Arg514 of ACE2 identified as influencing the potency of the ACE2-specific inhibitor MLN-4760. Consequently, important insights into the chloride sensitivity, substrate selectivity and inhibition of testicular ACE and ACE2 were elucidated.
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PMID:Residues affecting the chloride regulation and substrate selectivity of the angiotensin-converting enzymes (ACE and ACE2) identified by site-directed mutagenesis. 1902 74


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