Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While diabetes mellitus is most often associated with hypertension, dyslipidemia, and obesity, these factors do not fully account for the increased burden of cardiovascular disease in patients with the disease. This strengthens the need for comprehensive studies investigating the underlying mechanisms mediating diabetic cardiovascular disease and, more specifically, diabetes-associated atherosclerosis. In addition to the recognized metabolic abnormalities associated with diabetes mellitus, upregulation of putative pathological pathways such as advanced glycation end products, the renin-angiotensin system, oxidative stress, and increased expression of growth factors and cytokines have been shown to play a causal role in atherosclerotic plaque formation and may explain the increased risk of macrovascular complications. This review discusses the methods used to assess the development of atherosclerosis in the clinic as well as addressing novel biomarkers of atherosclerosis, such as low-density lipoprotein receptor-1. Experimental models of diabetes-associated atherosclerosis are discussed, such as the streptozocin-induced diabetic apolipoprotein E knockout mouse. Results of major clinical trials with inhibitors of putative atherosclerotic pathways are presented. Other topics covered include the role of HMG-CoA reductase inhibitors and fibric acid derivatives with respect to their lipid-altering ability, as well as their emerging pleiotropic anti-atherogenic actions; the effect of inhibiting the renin-angiotensin system by either ACE inhibition or angiotensin II receptor antagonism; the effect of glycemic control and, in particular, the promising role of thiazolidinediones with respect to their direct anti-atherogenic actions; and newly emerging mediators of diabetes-associated atherosclerosis, such as advanced glycation end products, vascular endothelial growth factor and platelet-derived growth factor. Overall, this review aims to highlight the observation that various pathways, both independently and in concert, appear to contribute toward the pathology of diabetes-associated atherosclerosis. Furthermore, it reflects the need for combination therapy to combat this disease.
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PMID:Diabetes mellitus-associated atherosclerosis: mechanisms involved and potential for pharmacological invention. 1648 46

Peripheral arterial disease (PAD) may be asymptomatic, may be associated with intermittent claudication or may be associated with critical limb ischaemia. Coronary artery disease (CAD) and other atherosclerotic vascular disorders may coexist with PAD. Persons with PAD are at increased risk for all-cause mortality, cardiovascular mortality and mortality from CAD. Smoking should be stopped and hypertension, diabetes mellitus, dyslipidaemia and hypothyroidism treated. HMG-CoA reductase inhibitors (statins) reduce the incidence of intermittent claudication and improve exercise duration until the onset of intermittent claudication in persons with PAD and hypercholesterolaemia. Antiplatelet drugs such as aspirin or clopidogrel (especially the latter), ACE inhibitors and statins should be given to all persons with PAD. beta-Adrenoceptor antagonists should be given if CAD is present. The phosphodiesterase type 3 inhibitor cilostazol improves exercise time until intermittent claudication. Chelation therapy should be avoided. Correct implementation of medical therapy significantly reduces the excess mortality associated with PAD. In addition, medical therapy may result in significant improvements in walking ability that may obviate the need for lower extremity angioplasty with stenting and bypass surgery.
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PMID:Drug treatment of peripheral arterial disease in the elderly. 1649 65

Essential fatty acids (EFAs)--linoleic acid (LA) and alpha-linolenic acid (ALA) are critical for human survival. EFAs are readily available in the diet. But, to derive their full benefit, EFAs need to be metabolized to their respective long-chain metabolites. EFAs not only form precursors to respective prostaglandins (PGs), thromboxanes (TXs), and leukotrienes (LTs), but also give rise to lipoxins (LXs), resolvins, isoprostanes, and hydroxy- and hydroperoxyeicosatetraenoates. Certain PGs, TXs, and LTs have pro-inflammatory actions whereas LXs and resolvins are anti-inflammatory in nature. Furthermore, EFAs and their long-chain metabolites modulate the activities of angiotensin converting and HMG-CoA reductase enzymes, enhance acetylcholine levels in the brain, increase the synthesis of endothelial nitric oxide, augment diuresis, and enhance insulin action. Thus, EFAs and their metabolites may function as endogenous ACE and HMG-CoA reductase inhibitors, nitric oxide enhancers, beta-blockers, diuretics, anti-hypertensive, and anti-atherosclerotic molecules. In addition, EFAs and their long-chain metabolites react with nitric oxide (NO) to yield respective nitroalkene derivatives that exert cell-signaling actions via ligation and activation of peroxisome proliferator-activated receptors (PPARs). Thus, EFAs and their derivatives have varied biological actions that may have relevance to their involvement in several physiological and pathological processes.
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PMID:Biological significance of essential fatty acids. 1694 15

New-onset diabetes mellitus in a previously non-diabetic transplant recipient is a serious adverse event that confers significant morbidity and mortality. The most significant consequences of post-transplant diabetes mellitus (PTDM) in solid organ transplant recipients include decreased patient and graft survival, an increased risk of infectious complications, and morbid cardiovascular events. The development of PTDM in the elderly is of particular concern because this group is already at increased risk of progression of cardiovascular disease. Because the elderly, especially those aged >65 years, are the fastest-growing segment of the renal transplant population, attention needs to be given to PTDM risk reduction and post-transplant management. PTDM develops as a consequence of both impaired insulin production and enhanced peripheral insulin resistance. A number of non-modifiable factors such as age, race, family history, hepatitis C, polycystic kidney disease and emerging genetic causes have been identified as risk factors for PTDM. However, a number of modifiable factors can be targets for intervention in high-risk patients, including bodyweight (through dietary restriction and exercise), hypertension, hyperlipidaemia and the effects of certain immunosuppressive agents. The two agents most responsible for PTDM are tacrolimus and corticosteroids, especially when used in combination. Attempts to modify doses and regimens designed to eliminate or avoid these drugs should be considered. Use of HMG-CoA reductase inhibitors ('statins') and ACE inhibitors is particularly helpful in controlling hypertension and hyperlipidaemia in the elderly because these agents confer protection against future adverse cardiovascular events. Bisphosphonates are also advantageous in controlling the progression of osteoporosis and possible increased risk of bone fractures. Future trials in the elderly should focus on such endpoints as PTDM, post-transplant neoplasia, cardiovascular events and bone fracture events in order to identify the safest regimens that provide the optimal control of rejection while limiting the morbidity from these secondary events.
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PMID:Post-transplant diabetes mellitus: risk reduction strategies in the elderly. 1706 82

Essential fatty acids (EFAs): cis-linoleic acid (LA) and alpha-linolenic acid (ALA) are essential for humans and their deficiency is rare in humans due to their easy availability in diet. EFAs are metabolized to their respective long-chain metabolites: dihomo-gamma-linolenic acid (DGLA), and arachidonic acid (AA) from LA; and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from ALA. Some of these long-chain metabolites form precursors to respective prostaglandins (PGs), thromboxanes (TXs), and leukotrienes (LTs), lipoxins (LXs) and resolvins. EFAs and their metabolites may function as endogenous angiotensin converting enzyme and HMG-CoA reductase inhibitors, nitric oxide enhancers, anti-hypertensives, and anti-atherosclerotic molecules. EFAs react with nitric oxide (NO) to yield respective nitroalkene derivatives that have cell-signaling actions via ligation and activation of peroxisome proliferator-activated receptors (PPARs). In several diseases such as obesity, hypertension, diabetes mellitus, coronary heart disease, alcoholism, schizophrenia, Alzheimer's disease, atherosclerosis, and cancer the metabolism of EFAs is altered. Thus, EFAs and their derivatives have significant clinical implications.
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PMID:Essential Fatty acids - a review. 1716 64

Atherosclerosis is a chronic inflammatory process. The adhesion of leukocytes to the vascular endothelium, mediated by endothelial cell adhesion molecules including vascular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin, is the pivotal early event in atherogenesis. Inflammatory cytokines could activate redox-sensitive transcription factors and induce endothelial expression of adhesion molecules, which could be inhibited to various degrees by different antioxidants suggesting the potential role of endogenous reactive oxygen species (ROS) in atherogenesis. Many clinical drugs that against cardiovascular diseases have exhibited antioxidant effects; these drugs simultaneously inhibit endothelial adhesion molecule expression, such as aspirin, probucol, HMG-CoA reductase inhibitors, angiotensin receptor blockers, angiotensin converting enzyme inhibitors, peroxisome proliferator-activated receptor alpha and gamma ligands, calcium channel blockers, beta-adrenergic blockers, etc. In addition, we have previously demonstrated that Ginkgo biloba extract, a Chinese herb with antioxidant activity, could significantly suppress inflammatory cytokine-stimulated endothelial adhesiveness to human monocytic cells by attenuating intracellular ROS formation, redox-senstive transcription factor activation, and VCAM-1 as well as ICAM-1 expression in human aortic endothelial cells. The similar anti-atherosclerosis effects have been also shown in other Chinese herbs or dietary supplements with antioxidant activity such as magnolol and salvianolic acid B either in vitro or in vivo. Thus, oxidative stress is critical to endothelial adhesiveness in atherogenesis. The inhibition of endothelial adhesion molecule expression by drugs/agents with antioxidant activity may serve as a potential therapeutic strategy for clinical atherosclerosis.
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PMID:Anti-inflammatory effects of different drugs/agents with antioxidant property on endothelial expression of adhesion molecules. 1737 73

Diabetes mellitus affects about 8% of the adult population. The estimated number of patients with diabetes, presently about 170 million people, is expected to increase by 50-70% within the next 25 years. Diabetes is an important component of the complex of 'common' cardiovascular risk factors, and is responsible for acceleration and worsening of atherothrombosis. Major cardiovascular events cause about 80% of the total mortality in diabetic patients. Diabetes also induces peculiar microangiopathic changes leading to diabetic nephropathy conducive to end-stage renal failure, and to diabetic retinopathy that may progress to vision loss and blindness. In terms of major cardiovascular events, coronary heart disease and ischaemic stroke are the main causes of morbidity and mortality in diabetic patients. Peripheral arterial disease frequently occurs, and is more likely to be conducive to critical limb ischaemia and amputation than in the absence of diabetes. Although there are a number of differences in the pathogenesis and clinical features of diabetic macroangiopathy and microangiopathy, these two entities often coexist and induce mutually worsening effects. Endothelial injury, dysfunction and damage are common starting points for both conditions. Causes of endothelial injury can be distinguished into those 'common' to nondiabetic atherothrombosis, such as hypertension, dyslipidaemia, smoking, hypercoagulability and platelet activation; and those more specific and in some cases 'unique' to diabetes and directly related to the metabolic derangement of the disease, such as (i) desulfation of glycosaminoglycans (GAGs) of the vascular matrix; (ii) formation of advanced glycation end-products (AGE) and their endothelial receptors (RAGE); (iii) oxidative and reductive stress; (iv) decline in nitric oxide production; (v) activation of the renin-angiotensin aldosterone system (RAAS); and (vi) endothelial inflammation caused by glucose, insulin, insulin precursors and AGE/RAGE. Prevention of major cardiovascular events with the antithrombotic agent aspirin (acetylsalicylic acid) is widely recommended, but reportedly underutilised in patients with diabetes. However, some data suggest that aspirin may be less effective than expected in preventing cardiovascular events and especially mortality in patients with diabetes, as well as in slowing progression of retinopathy. In contrast, a recent study found picotamide, a direct thromboxane inhibitor, to be superior to aspirin in diabetic patients. Clopidogrel was either equivalent or less active in diabetic versus nondiabetic patients, depending upon different clinical settings.Recent studies have shown that some GAG compounds are able to reduce micro- and macroalbuminuria in diabetic nephropathy, and hard exudates in diabetic retinopathy, but it is as yet unknown whether these agents also influence the natural history of microvascular complications of diabetes. Lifestyle changes and physical exercise are also essential in preventing cardiovascular events in diabetic patients. Available data on the control of the metabolic state and the main risk factors show that careful adjustment of blood sugar and glycated haemoglobin is more effective in counteracting microvascular damage than in preventing major cardiovascular events. The latter objective requires a more comprehensive approach to the whole constellation of risk factors both specific for diabetes and common to atherothrombosis. This approach includes lifestyle modifications, such as dietary changes and smoking cessation and the use of HMG-CoA reductase inhibitors (statins), which are able to correct the lipid status and to prevent major cardiovascular events independently of the baseline lipidaemic or cardiovascular status. Tight control of hypertension is essential to reduce not only major cardiovascular events but also microvascular complications. Among antihypertensive measures, blockade of the RAAS by means of ACE inhibitors or angiotensin II receptor antagonists recently emerged as a potentially polyvalent approach, not only for treating hypertension and reducing cardiovascular events, but also to prevent or reduce albuminuria, counteract diabetic nephropathy and lower the occurrence of new type 2 diabetes in individuals at risk.
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PMID:Approaches to prevention of cardiovascular complications and events in diabetes mellitus. 1748 45

Acute coronary syndromes (ACS) present a major health challenge in modern medicine. With new clinical trials being conducted, our knowledge of latest therapies for ACS continually evolves. In this article, we review currently available medical therapies and provide evidence-based rationale for current pharmacologic therapies. Among the antiplatelet therapies, aspirin, clopidogrel, and glycoprotein IIb/IIIa inhibitors demonstrate significant efficacy in reducing morbidity and mortality. Among the anticoagulants, unfractionated heparin and low molecular weight heparin, particularly enoxaparin sodium, remain the hallmarks of therapy against which newer anticoagulants are often compared. Bivalirudin has recently showed significant efficacy in decreasing cardiovascular events and mortality, but with potentially less risk of bleeding than heparin. Results of trials evaluating warfarin remain inconsistent regarding potential benefits. Finally, fondaparinux sodium, recently tested, shows promise as a powerful yet safe anticoagulant. Fibrinolysis is an acceptable modality for reperfusion if facilities equipped for primary percutaneous revascularization are not available. Regarding anti-ischemic therapy, beta-adrenoceptor antagonists and nitrates remain critical in the early management of ACS. Inhibitors of the renin-angiotensin-aldosterone system have also shown significant reductions in the morbidity and mortality of patients presenting with ACS, particularly in patients with left ventricular dysfunction and clinical heart failure, with ACE inhibitors being first-line agents and angiotensin receptor antagonists being a reasonable substitute if ACE inhibitors are not tolerated. Among the lipid-lowering therapies, statins (HMG-CoA reductase inhibitors) have been documented as being the most well tolerated and most efficacious therapies for ACS patients and data exist that they should be administered early in ACS management. Studies evaluating combination therapy (antiplatelet drugs, beta-adrenoceptor antagonists, ACE inhibitors, and lipid-lowering agents) show a clear benefit in mortality in patients with known coronary artery disease. Efforts to improve these key evidence-based medical therapies are numerous and include such programs as the American College of Cardiology's Guidelines Applied in Practice, international patient registries such as the Global Registry of Acute Coronary Events, and studies such as CRUSADE. Finally, patients with diabetes mellitus pose a challenge to clinicians both in terms of their glycemic control and in their apparent relative resistance to antiplatelet therapy. Studies involving ACS patients suggest that stringent glycemic control may result in benefits in both morbidity and mortality.
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PMID:Evidence-based medical therapy of patients with acute coronary syndromes. 1750 81

Elevated plasma concentrations of homocysteine, a sulfur-containing amino acid, are a risk factor for coronary, cerebral and peripheral artery disease. Next to other factors, drugs used for the prevention or treatment of cardiovascular disease may modulate plasma homocysteine levels. Thus, a drug induced homocysteine increase may counteract the desired cardioprotective effect. The aim is to summarize the current knowledge on the effect of two important classes of drugs, lipid-lowering drugs and anti-hypertensive drugs, on homocysteine metabolism. Among the lipid-lowering drugs, especially the fibric acid derivatives, which are used for treatment of hypertriglyceridemia and low HDL-cholesterol, are associated with an increase of homocysteine by 20%-50%. This increase can be reduced, but not totally avoided by the addition of folic acid, vitamin B12 and B6 to fibrates. HMG-CoA reductase inhibitors (statins) do not influence homocysteine concentrations substantially. The effects of nicotinic acid and n3-fatty acids on the homocysteine concentrations are less clear, more studies are necessary to clarify their influence on homocysteine. Antihypertensive drugs have also been studied with respect to homocysteine metabolism. A homocysteine increase has been shown after treatment with hydrochlorothiazide, a lowering was observed after treatment with beta-blockers, but no effect with ACE-inhibitors. The clinical significance of the homocysteine elevation by fibrates and thiazides is not clear. However, individual patients use these drugs for long time, indicating that even moderate increases may be important.
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PMID:Effect of lipid-lowering and anti-hypertensive drugs on plasma homocysteine levels. 1758 80

Atrial fibrillation is the most common postoperative arrhythmia with significant consequences on patient health. Postoperative atrial fibrillation (POAF) complicates up to 8% of all noncardiac surgeries, between 3% and 30% of noncardiac thoracic surgeries, and between 16% and 46% of cardiac surgeries. POAF has been associated with increased morbidity, mortality, and longer, more costly hospital stays. The risk of POAF after cardiac and noncardiac surgery may be affected by several epidemiologic and intraoperative factors, as well as by the presence of preexisting cardiovascular and pulmonary disorders. POAF is typically a transient, reversible phenomenon that may develop in patients who possess an electrophysiologic substrate for the arrhythmia that is present before or as a result of surgery. Numerous studies support the efficacy of beta-blockers in POAF prevention; they are currently the most common medication used in POAF prophylaxis. Perioperative amiodarone, sotalol, nondihydropyridine calcium channel blockers, and magnesium sulfate have been associated with a reduction in the occurrence of POAF. Biatrial pacing is a nonpharmacologic method that has been associated with a reduced risk of POAF. Additionally, recent studies have demonstrated that hydroxymethylglutaryl-CoA reductase inhibitors may decrease the risk of POAF. Finally, based on recent evidence that angiotensin converting enzyme inhibitors and angiotensin receptor blockers reduce the risk of permanent atrial fibrillation, these medications may also hold promise in POAF prophylaxis. However, there is a need for further large-scale investigations that incorporate standard methodologies and diagnostic criteria, which have been lacking in past trials.
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PMID:The changing face of postoperative atrial fibrillation prevention: a review of current medical therapy. 1770 Mar 82


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