Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reviewed are various aspects of atherosclerotic plaque stabilization and regression in humans and experimental animals. Plaque regression is a function of the dynamic balance among initiation, progression, stabilization, and removal of plaque constituents. Pseudoregression, the result of the triad thrombolysis, age- or lesion-dependent arterial dilatation, and relaxation of vasospasm, may readily give rise to angiographic misinterpretation. Although lowering of plasma cholesterol and low density lipoprotein-cholesterol has demonstrated significant clinical benefits in a number of clinical trials, the magnitude of angiographic regressive changes is relatively small despite aggressive lipid-lowering regimens. The emerging need for alternative or complementary therapeutic interventions has been emphasized. In particular, they should be targeted to pivotal cellular or molecular mechanisms in initiation, progression, or stabilization. Potentially important therapeutic targets include the use of antioxidants or free radical scavengers such as Probucol or its analogues, butylated hydroxytoluene, tocopherols, and possibly the tocotrienols. Other therapeutic targets include intimal monocyte-macrophage recruitment, macrophage cholesterol acyltransferase inhibition, stimulation of the high density lipoprotein-mediated reverse cholesterol transport system, smooth muscle cell migration to and proliferation in the arterial intima, and intimal connective tissue synthesis. Whether the isoprenylated proteins associated with the cholesterol biosynthetic pathway will give rise to compounds regulating smooth muscle cell growth has yet to be determined. Because of the importance of thrombosis in the pathogenesis and progression of lesions, the need to develop interventional strategies targeted at endothelial cell thromboresistance and thromboregulation must assume a high priority in future research and development. Other areas of therapeutic promise include the calcium channel blockers and angiotensin converting enzyme inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Atherosclerosis. Potential targets for stabilization and regression. 142 45

Lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) are key factors in the esterification of free cholesterol, and the distribution of cholesteryl ester among lipoproteins in plasma. Alterations in these processes may play a role in the lipoprotein abnormalities associated with glomerular proteinuria. The activities of LCAT and CETP were measured using excess exogenous substrate assays in nine patients with nephrotic-range proteinuria and in 18 matched controls. The proteinuria-lowering effect of four weeks of angiotensin converting enzyme (ACE) inhibition with enalapril was also studied. Plasma very low lipoprotein and low density lipoprotein (VLDL and LDL) cholesterol, triacylglycerol and apolipoprotein B levels were significantly elevated in the patients compared with controls. High density lipoprotein (HDL) total cholesterol, free cholesterol, cholesteryl ester and the free cholesterol/cholesteryl ester ratio in HDL were lower. Total plasma apolipoprotein A1 was normal. Plasma LCAT and CETP activities were elevated in the patients by 30% (P < 0.01) and by 39% (P < 0.01), respectively, and were both inversely related to serum albumin. VLDL and LDL cholesterol levels were positively related to LCAT and CETP activities, whereas the HDL free cholesterol content was inversely related to LCAT activity. ACE inhibition resulted in a 40% reduction of proteinuria, a partial normalization of LCAT activity, and a decrease in VLDL and LDL cholesterol. In conclusion, elevated activities of LCAT and CETP may provide a mechanism that contributes to the low proportion of cholesterol in HDL relative to that in VLDL and LDL, as well as to the compositional changes of HDL seen in glomerular proteinuria.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of elevated lecithin: cholesterol acyltransferase and cholesteryl ester transfer protein activities in abnormal lipoproteins from proteinuric patients. 835 71

Essential hypertension is, at least in many subjects, associated with a decrease in insulin sensitivity, whereas glycemic control is (still) normal. Metaanalyses of hypertension intervention studies revealed different efficacy of treatment on cerebral (cerebrovascular accidents [CVA]) and cardiac (coronary heart disease [CHD]) morbidity and mortality. Although CVA were reduced to an extent similar to that anticipated, the decrease in CHD was less than expected. These differences are likely to be caused by the different impact of concomitant cardiovascular risk factors, such as dyslipidemia, impaired glucose tolerance, and non-insulin-dependent diabetes mellitus on CHD and CVA. Frequently these cardiovascular risk factors are ineffectively controlled in hypertensive patients, and moreover, some of the widely used antihypertensive agents have unfavorable side effects and further deteriorate these particular metabolic risk factors. Therefore, the metabolic side effects of antihypertensive treatment have received more attention. During the past few years, studies demonstrated that most antihypertensive agents modify insulin sensitivity in parallel with alterations in the atherogenic lipid profile. Alpha1-blockers and angiotensin converting enzyme inhibitors were shown to either have no impact on or even improve insulin resistance and the profile of atherogenic lipids, whereas most of the calcium channel blockers were found to be metabolically inert. The diuretics and beta-adrenoreceptor antagonists further decrease insulin sensitivity and worsen dyslipidemia. The mechanisms by which beta-adrenoreceptor antagonist treatment exert its disadvantageous effects are not fully understood, but several possibilities exist: significant body weight gain, reduction in enzyme activities (muscle lipoprotein lipase and lecithin cholesterol acyltransferase), alterations in insulin clearance and insulin secretion, and, probably most important, reduced peripheral blood flow due to increase in total peripheral vascular resistance. Recent metabolic studies found beneficial effects of the newer vasodilating beta-blockers, such as dilevalol, carvedilol and celiprolol, on insulin sensitivity and the atherogenic risk factors. In many hypertensive patients, elevated sympathetic nerve activity and insulin resistance are a deleterious combination. Although conventional beta-blocker treatment was able to take care of the former, the latter got worse; the newer vasodilating beta-blocker generation seems to be capable of successfully treating both of them.
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PMID:Antihypertensive therapy and insulin sensitivity: do we have to redefine the role of beta-blocking agents? 979 45