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

A universal underlying abnormality in the pathogenesis of hypertension, atherosclerosis, myocardial dysfunction, and diabetic glomerulosclerosis involves alteration in smooth muscle cell structure, function, and growth. Angiotensin II, through its effects on contractility, growth, and the sympathetic nervous system, may potentially play a key role in this pathologic process and, thus, contribute to the development of these cardiovascular and renal complications of diabetes mellitus. Angiotensin-converting enzyme inhibitors and some direct renin inhibitors prevent or slow the progression of some of these complications, which further suggests a pathologic role for the reninangiotensin system in diabetes mellitus.
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PMID:Effect of the renin-angiotensin system in the vascular disease of type II diabetes mellitus. 158 Feb 75

From pharmacologic investigations and clinical studies it is known that angiotensin-converting enzyme (ACE) inhibitors exhibit additional local actions, which are not related to hemodynamic changes and which cannot be explained simply by interference with the renin-angiotensin system with subsequent inhibition of angiotensin II formation. Because ACE is identical to kininase II, which inactivates the nonapeptide bradykinin (BK), potentiation of BK might be responsible for these additional effects of ACE inhibitors. To prove the specificity of BK-mediated effects by ACE inhibition, we used the specific B2 kinin receptor antagonist HOE 140 in different models: endothelial cell cultures; atherosclerosis in high-cholesterol-fed rabbits; neointima formation with smooth cell proliferation and migration after endothelial denudation in rats; myocardial ischemia in rats, rabbits, and dogs; and left ventricular hypertrophy in rats. The beneficial effects of ramipril or BK given in non-blood pressure-lowering doses in these models were abolished by HOE 140 (icatibant). Ramipril exerts cardioprotective effects in different experimental models. The formation of the endothelial autacoids nitric oxide and prostacyclin, enhanced when BK degradation is inhibited by ACE inhibition, may contribute to the observed beneficial effects.
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PMID:Contribution of bradykinin to the cardiovascular effects of ramipril. 751 34

Angiotensin-converting enzyme inhibitors have been extensively studied and established in the treatment of hypertension, heart failure, and ventricular dysfunction. They have various cardiac and vascular protective effects, but the relevant mechanisms of action in these areas remain to be fully understood. Possible effects of converting-enzyme inhibition related to maintenance of normal endothelial function and inhibition of atherosclerosis should be distinguished from effects on myointimal proliferation related to vascular injury and regression of vascular hypertrophy from blood pressure reduction. Experimental animal studies have showed benefit from converting-enzyme inhibition in preventing myointimal proliferation after vascular injury in some species, but no such effect has been shown in clinical studies of restenosis following coronary angioplasty. Laboratory studies have demonstrated a protective effect of converting-enzyme inhibition on endothelial vasomotor function. Further studies have demonstrated prevention of atherosclerosis in hyperlipidemic rabbits and cholesterol-fed cynomolgus monkeys. Possible mechanisms of action apart from blood pressure lowering include inhibition of angiotensin II and other tissue growth factors and accumulation of kinins. These data, among others, provide sufficient rationale for clinical studies to determine whether converting-enzyme inhibitors can reduce atherosclerotic disease and thus widen their application as cardiac and vascular protective agents.
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PMID:The effects of ACE inhibition on progression of atherosclerosis. 751 40

From pharmacological investigations and clinical studies, it is known that ACE inhibitors exhibit additional local actions that are not related to hemodynamic changes and that cannot be explained only by interference with the renin-angiotensin system by means of an inhibition of ANG II formation. Because ACE is identical to kininase II, which inactivates the nonapeptide BK and related kinins, potentiation of kinins might be responsible for these additional effects of ACE inhibitors. ACE inhibition, concentration, and time dependently increased the formation of NO and PGI2 in cultured endothelial cells of different origin and from different species, including humans. The specific B2 kinin receptor antagonist, icatibant, suppressed the ACE inhibitor-induced increase in endothelial cyclic GMP accumulation index for NO-formation and, in parallel, attenuated the increase in PGI2 release. In renovascular models of hypertension associated with a stimulated renin-angiotensin system (two-kidney, one-clip), blood pressure reduction by ACE inhibitors was attenuated by icatibant, whereas in rats with genetic hypertension with normal to low plasma renin, blood pressure reduction through ACE inhibitors was not affected. In experimental atherosclerosis in rabbits, ACE inhibitors were able to preserve endothelial function and vascular reactivity and to reduce surface involvement. In the balloon denudation model of carotid arteries in rats, it was found that ACE inhibition markedly reduced neointima formation. However, when the ACE inhibitor was given together with icatibant, its effect was significantly blunted. Perfusion with ACE inhibitors induced a reduction of the incidence, as well as of the duration, of ventricular fibrillation and improved cardiodynamics and myocardial metabolism. BK perfusion induced comparable cardioprotective effects. In addition, perfusion with ACE inhibitors markedly increased the outflow of BK and related kinins from isolated rat hearts. The antiischemic effect of ACE inhibitors and BK were abolished by the addition of L-NNA (1 x 10(-6) mol/l) or icatibant (1 x 10(-9) mol/l). Similar results were found in dogs and rabbits with myocardial infarction. BK and related kinins also seem to be involved in preconditioning and remodeling. The effect of ACE inhibition in LVH was investigated in rats made hypertensive by aortic banding. ACE inhibition with ramipril, in the antihypertensive dose of 1 mg/kg/day for 6 weeks, prevented the increase in blood pressure and the development of LVH. A lower, nonantihypertensive dose of the ACE inhibitor (10 micrograms/kg/day for 6 weeks) had no effect on the increase in blood pressure or on plasma ACE activity, but also prevented LVH after aortic banding.4+ off
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PMID:Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. 778 79

The effect of two angiotensin converting enzyme (ACE) inhibitors on the development of atherosclerosis was determined in hyperlipidemic hamsters. Preliminary studies indicated that only fosinopril (50 mg/kg) temporarily decreased mean arterial pressure, while after chronic dosing fosinopril and captopril (50 mg/kg) were ineffective. The same dose of fosinopril and captopril inhibited the angiotensin I pressor response, indicating these agents suppressed ACE activity in vivo. In the 3 week atherosclerosis experiment, all hamsters were fed chow supplemented with 0.05% cholesterol and 10% coconut oil. Control hamsters were compared with those receiving either 50 mg/kg per day of fosinopril or 50 mg/kg per day of captopril. After 3 weeks, fosinopril reduced plasma total cholesterol, low density lipoprotein (LDL) plus very low density lipoprotein cholesterol and total triglycerides by 17%, 27% and 45%, respectively. Captopril only reduced high density lipoprotein cholesterol by 20%. Neither fosinopril or captopril altered blood pressure at 3 weeks. Atherosclerosis was quantified from en face preparations of the lesion-prone aortic arch that were stained with oil red O (for cholesteryl ester and triglycerides). In control hamsters, oil red O labeled numerous subendothelial macrophage-foam cells located along the inner curvature of the aortic arch. Compared with controls, fosinopril reduced the number of intimal macrophage-foam cells/mm2, foam cell size and the fatty streak area by 85%, 38% and 90%, respectively. Captopril decreased these parameters by 44%, 16% and 53%. Thus captopril decreased early atherosclerosis without affecting plasma LDL cholesterol or blood pressure, which suggested that inhibiting ACE (or kininase II) directly impeded the accumulation and formation of macrophage-foam cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Atherosclerosis 1994 Jul
PMID:Inhibitors of angiotensin converting enzyme decrease early atherosclerosis in hyperlipidemic hamsters. Fosinopril reduces plasma cholesterol and captopril inhibits macrophage-foam cell accumulation independently of blood pressure and plasma lipids. 798 Jul 8

The association between hypertension and atherosclerosis is complex, incorporating endothelial dysfunction, abnormalities of insulin and lipid metabolism, altered vascular biology, and impaired arterial compliance. Results of experimental and human studies suggest that there is heterogeneity in the manifestations of disease and responses to therapy among different animal species, vascular territories, and individual patients. Antihypertensive therapy requires the careful selection of specific agents that reduce blood pressure and preferentially and positively modulate the synergistic interaction of the many facets of disease, with the goal of preventing or regressing atherosclerosis. Angiotensin-converting enzyme (ACE) inhibitors, calcium antagonists, and alpha-blockers appear to hold the greatest promise in this regard.
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PMID:Differential effects of antihypertensive agents in experimental and human atherosclerosis. 846 24

An insertion(I)/deletion(D) polymorphism in the angiotensin I-converting enzyme (ACE) gene seems to be associated with clinical heart disease in patients with diabetes mellitus. It is not known whether increased atherosclerosis or other factors among individuals with certain ACE-gene subtypes form the basis for the increased prevalence of heart disease among these subjects. We measured, at autopsy, the extent of macroscopically visible aortic atherosclerosis in 22 diabetic and 39 non-diabetic subjects and determined the ACE-genotype of all individuals by the polymerase chain reaction. The percentage of aortic surface area covered with atherosclerotic lesions was 29 +/- 8 (n = 6), 71 +/- 7 (n = 9), and 65 +/- 7 (n = 5) in the II-, ID-, and DD-genotype subgroups, respectively, among diabetes patients (mean +/- SEM) (2 p < 0.01, when comparing values from the ID and DD groups to the II group). The values were 37 +/- 9 (n = 11), 40 +/- 5 (n = 14) and 37 +/- 6 (n = 11) in the II-, ID-, and DD-genotypes in the non-diabetic group. There were no differences in sex ratio or age in any of the ACE-gene subtypes. The previously described relationship between heart disease and the ACE-gene polymorphism in diabetes could thus be founded in an increased extent of atherosclerosis among patients with the ID- and DD-ACE-gene subtypes. Patients with diabetes have several alterations in the composition of the collagenous components in the arterial wall. We also analysed for associations between total collagen and type IV and type V collagen content in the aortic vessel wall and the ACE-gene subtypes. We were, however, not able to disclose correlations between the polymorphism and any of these parameters. In conclusion, our data show an association between the ACE-I/D polymorphism and the degree of aortic atherosclerosis in diabetes; however, we did not observe correlations between the polymorphism and data concerning arterial collagenous components.
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PMID:Aortic atherosclerosis in diabetes mellitus is associated with an insertion/deletion polymorphism in the angiotensin I-converting enzyme gene. No relation between the polymorphism and aortic collagen content. 878 65

The D allele of an insertion/deletion (I/D) polymorphism in the angiotensin I-converting enzyme (ACE) gene is associated with a risk of myocardial infarction, and the relative risk associated with the ACE D allele is increased by the C allele of an angiotensin II type 1 receptor (AT1R) gene polymorphism (an A-->C transversion at nucleotide position 1166) [28]. The relation of the ACE and AT1R gene polymorphisms to coronary heart disease and the severity of coronary artery stenosis has now been investigated in 133 patients with myocardial infarction (MI) or angina pectoris who underwent coronary angiography and in 258 control subjects. The frequency of the ACE DD genotype as compared with non-DD was significantly higher in the patients who experienced an MI and in the low-risk patients than that in the controls (P < 0.05). The DD genotype showed a significantly increased risk of MI (odds ratio 1.85). The frequency of the AT1R A/C genotypes did not differ between the patients and the controls. The severity of coronary stenosis in the patients was estimated by the number of affected vessels (> 75% stenosis) and the coronary score of Gensini. Neither the number of affected vessels nor the coronary score differed among the ACE I/D genotypes. However, the number of affected vessels was significantly greater in patients with the AT1R AC genotype than in those with the 4A genotype (1.93 +/- 0.27 vs. 1.27 +/- 0.99; P < 0.05) (CC genotype was not found in the patients). After excluding patients with diabetes mellitus, the coronary score of those with the AC genotype was also significantly higher than in those with the AA genotype (51.7 +/- 34.4 vs. 18.2 +/- 23.3; P < 0.01). These results suggest that the ACE D allele is associated with the occurrence of myocardial infarction, while the AT1R C allele is involved in the development of the coronary artery stenosis.
Atherosclerosis 1996 Sep 06
PMID:Significance of angiotensin I-converting enzyme and angiotensin II type 1 receptor gene polymorphisms as risk factors for coronary heart disease. 884 48

Abnormal growth of vascular smooth-muscle cells is a characteristic of many cardiovascular diseases. This abnormal growth occurs during hypertension-induced vascular hypertrophy, during the development of an atherosclerotic lesion, and during the development of a restenotic lesion following angioplasty. It is becoming increasingly apparent that among the many factors that may influence vascular structure, angiotensin may play a major role. Angiotensin-converting enzyme (ACE) inhibitors decrease hypertension-induced vascular hypertrophy, and, in many animal models, these inhibitors block the development of atherosclerosis and the development of an injury-induced neointimal lesion. Evidence suggests that the local production of angiotensin via tissue-converting enzyme may play an important role in these growth effects. We have demonstrated in animal models that injured vessels express high levels of ACE. Moreover, we have shown that the ability of an ACE inhibitor to block neointimal development correlates better with its ability to inhibit tissue ACE than with its ability to block circulating ACE. The role of angiotensin in human atherosclerosis is not clear. In an immunohistochemical study of human coronary arteries, we have obtained evidence that ACE is present within the atherosclerotic plaque, associated with regions of macrophage clustering. Moreover, in cell culture, monocytes induced to differentiate into macrophages express high levels of ACE. Treatment of these cells with acetylated low density lipoproteins results in a further increase in ACE expression. These results support the hypothesis that ACE may play a role in the development of atherosclerosis. Further studies, however, are required to precisely define this role.
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PMID:Regulation of vascular smooth-muscle cell growth by angiotensin II. 891 33

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


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