他汀类药物的调脂外作用

他汀类 (ｓｔａｔｉｎｓ)药物 ,现已广泛应用于高胆固醇血症的治疗。它竞争性抑制ＨＭＧ ＣｏＡ还原酶 ,具有比其它降胆固醇药更好的降低密度脂蛋白 (ＬＤＬ)作用。随着对他汀类药物临床作用更深入的研究 ,发现他汀类药物对冠心病的一级预防及二级预防有益 ,但这些作用尚不能完全由基础及治疗后ＬＤＬ浓度来解释。目前认为 ,他汀类药物临床作用的可能机制包括抑制血管平滑肌细胞增殖 ,改善内皮功能 ,稳定斑块的生理化学特性 ,抑制血小板血栓形成以及抗炎症反应。1　对血管平滑肌细胞的作用血管平滑肌细胞 (ＶＳＭＣ)增殖、迁移及表型与功能…     

阿托伐他汀的非调脂作用

他汀类降血脂药物为 3羟基 3 甲基戊二酰辅酶Ａ(ＨＭＧ ＣｏＡ)还原酶抑制剂 ,其部分结构与ＨＭＧ ＣｏＡ还原酶的基质ＨＭＧ ＣｏＡ结构相似 ,可与ＨＭＧ ＣｏＡ竞争与酶的活性部分结合 ,从而阻碍ＨＭＧ ＣｏＡ还原酶的作用 ,后者是胆固醇合成过程中的限速酶 ,因而胆固醇的合成受抑制 ,血胆固醇水平降低 ,细胞内胆固醇含量减少又可刺激细胞表面低密度脂蛋白 (ＬＤＬ)受体合成增加 ,从而促进ＬＤＬ、极低密度脂蛋白 (ＶＬＤＬ)通过受体途径代谢 ,降低血清ＬＤＬ含量 ,其副作用有乏力、肌痛、胃肠道症状、皮疹等。目前临床应用其第一代产品如…     

Endothelium-dependent effects of statins

The vascular endothelium is a dynamic endocrine organ that regulates contractile, secretory, and mitogenic activities in the vessel wall and hemostatic processes within the vascular lumen. Risk factors for cardiovascular disease, such as cigarette smoking, hypertension, and elevated serum lipid levels, impair endothelial function and lead to the development of atherosclerotic vessels. Recent studies suggest that statins reduce cardiovascular events in part by improving endothelial function. Statins reduce plasma cholesterol levels, thereby decreasing the uptake of modified lipoproteins by vascular wall cells. There is increasing evidence, however, that statins may also exert effects beyond cholesterol lowering. Indeed, many of these cholesterol-independent or "pleiotropic" vascular effects of statins appear to involve restoring or improving endothelial function through increasing the bioavailability of nitric oxide, promoting re-endothelialization, reducing oxidative stress, and inhibiting inflammatory responses. Thus, the endothelium-dependent effects of statins are thought to contribute to many of the beneficial effects of statin therapy in cardiovascular disease.     

Immunosuppressive effects of statins

3-Hydroxy-3-methhylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are effective lipid lowering agents, extensively used in medical practice [Circulation 2000;101:207; J Am Med Assoc 2000;283:2935]. Statins have never been shown to be involved in the immune response, although reports have suggested a better outcome of cardiac transplantation in patients under pravastatin therapy [New Engl J Med 1995;333:621; Circulation 1997;96:1398]. Major histocompatibility complex class II (MHC class II) molecules are directly involved in the activation of T lymphocytes and in the control of the immune response. Whereas only a limited number of specialized cell types express MHC-II constitutively, numerous other cells become MHC-II positive upon induction by interferon-gamma (IFN-gamma) [Annu Rev Immunol 1996;14:301]. This complex regulation is under the control of the transactivator CIITA [Science 1994;265:106]. Recently, we demonstrated that statins act as direct inhibitors of induction of MHC-II expression by IFN-gamma and thus as repressors of MHC-II-mediated T cell activation [Nat Med 2000;6:1399; Swiss Med Wkly 2001;131:41]. This effect of statins is due to inhibition of the inducible promoter IV of the transactivator CIITA. Interestingly, this inhibition is specific for inducible MHC-II expression and does not concern constitutive expression of CIITA and MHC-II. In repressing induction of MHC-II, and subsequent T lymphocyte activation, statins therefore behave as a novel type of immunomodulator. This unexpected effect provides a scientific rationale for suggesting the use of statins as novel immunosuppressors, not only in organ transplantation but in numerous other pathologies as well.     

Pleiotropic effects of statins

The advent of statin therapy has revolutionized the ability of the clinician to manage patients at risk for the development of an ischemic event due to dyslipidemia. Large-scale clinical trials involving thousands of patients in both primary and secondary prevention have clearly demonstrated that statin therapy will reduce cardiovascular mortality across a broad spectrum of patient subgroups. Additionally, in adequately powered trials, total mortality has been successfully decreased by the use of statin therapy. However, the precise mechanism underlying the benefit of statin therapy has been controversial due to the multiplicity of potential benefits that statins have demonstrated in addition to pure lipid lowering. The causal theory of pharmacologic benefit reiterates the lipid hypothesis, which states that dyslipidemia is central to the process of atherosclerosis and the clinical benefit which accrues from statin therapy is a function of the degree of lipid lowering. The noncausal theory supports the premise that clinical benefits are related primarily to pleiotropic effects of statins (endothelial function, inflammation, coagulation and plaque vulnerability) as being the major modulators of clinical benefit. This review will focus on the potential beneficial effects of statin therapy on a number of the pleiotropic effects of statins and the potential role that these activities play in the reduction of risk for ischemic events.     

Pleiotropic effects of statins

Systematization of pleiotropic actions of statins is presented with special stress on effects important for prevention of atherosclerotic diseases, nonatherosclerotic cardiovascular diseases, and diseases of noncardiovascular origin. Dependence of pleiotropic effects of statins on dose and duration of administration is shown. The review contains data on novel studies of pleiotropic effects favorably affecting endothelial function, oxidative stress, arterial pressure, angiogenesis, heart failure, and disturbances of cardiac rhythm.     

他汀类药物的血管保护作用

他汀类药物是一种3-羟基-3-甲基戊二酰辅酶A（HMG,CoA）还原酶抑制剂,通过抑制胆固醇合成过程中的限速酶-HMG—CoA还原酶而降低胆固醇和低密度脂蛋白。近期研究发现他汀类药物具有独立于降脂以外的修复血管损伤的作用,包括抗炎、抗氧化、修复内皮、促新生血管生成、稳定斑块等。     

他汀类药物抗心律失常作用的研究

他汀类药物除具调脂作用外,还有广泛的调脂外作用,并能预防冠心病患者发生室性心律失常,降低心脏性猝死的危险.近年来的研究表明,他汀类药物可抑制颤动心房的电重构和结构重构,降低心房颤动发生和预防心房颤动转律后的复发.本文对近年来他汀类药物在室性心律失常和心房颤动方面的研究作一综述.     

The pleiotropic effects of statins

PURPOSE OF REVIEW: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the most widely prescribed drugs worldwide for lowering cholesterol levels. In use for more than 15 years, they have demonstrated efficacy, safety, and tolerability across a broad range of patients. This class of drugs has been designed to lower the cholesterol level by competitively inhibiting the enzyme responsible for its biosynthesis and thereby to play a major role in reducing cardiovascular risk. However, both basic evidence and clinical evidence also supports the idea that reductions in cardiovascular risk are dependent on mechanisms beyond cholesterol reduction alone, such as the reduction of endothelial dysfunction, inhibition of inflammatory responses, stabilization of atherosclerotic plaques, and modulation of procoagulant activity and platelet function. RECENT FINDINGS: In fact, as shown in several clinical trials, the beneficial effects of statin treatment begin earlier than its cholesterol-lowering effect. These other mechanisms could act in concert with the potent low-density lipoprotein cholesterol-lowering effects of this class of drugs to exert early and lasting cardiovascular protective effects. Recently, several studies have shown that an intensive lipid-lowering regimen with a statin provides greater protection against death or major cardiovascular events than does a standard regimen. SUMMARY: This review summarizes the new findings in these pleiotropic effects and describes their impact on vascular processes.     

The cardioprotective effects of statins

In addition to their lipid-modulating properties, statins have a large number of beneficial cardiovascular effects that have emerged over time and that were not anticipated during drug development. The lipid and nonlipid effects act in a concerted way to reduce the ischemic burden of the myocardium and to protect it against injury. By acting on the vessel wall, statins may prevent lesion initiation and repair injuries, enhance myocardial perfusion, slow lesion progression, and prevent coronary occlusion. They may also directly reduce myocardial damage, favor myocardial repair, and protect against immune injury. This review focuses on properties of statins that contribute to their cardioprotective effect. The first section includes information on modulation of vascular tone, endothelial permeability and function, inhibition of complement injury, curbing of foam cell formation, antioxidant and anti-inflammatory properties, and profibrinolytic and anticoagulant activities. The second section relates to reduction of myocardial necrosis, myocardial hypertrophy, blood pressure, and heart failure, as well as mobilization of endothelial progenitor cells for repair, angiogenic effects, and immunomodulation. In many instances, results of in vitro and animal studies have raised expectations and prompted studies in humans. Several clinical trials have confirmed these expectations and have strengthened the value of statins as valuable antiatherosclerotic and cardioprotective agents.     

The cardioprotective effects of statins

Many large randomized clinical trials have demonstrated that statins are effective in terms of prevention of cardiovascular events. It has been presumed that these beneficial effects could be due to not only improved plasma lipid profiles but also to the direct actions on the vascular wall. In addition to the direct vascular protective effects, several lines of experimental evidence have been accumulated that statins have also cardioprotective effects against ischaemia/reperfusion injury. This effect appears to be a class-effect and activation and up-regulation of eNOS by statins play an important role.     

The antioxidant effects of statins

Oxidative stress contributes to the initiation and the development of atherosclerotic plaques and adversely influences myocardial integrity. Statins interfere with oxidation in several ways that may contribute to reducing the atherogenic process. In addition to direct antioxidant effects, statins reduce circulating oxidized low-density lipoproteins (oxLDL) and inhibit their uptake by macrophages. They also reduce circulating markers of oxidation such as F2-isoprostane and nitrotyrosine. Statins inhibit oxidant enzymes activity such as that of reduced nicotinamide adenine dinucleotide phosphate (NAD[P]H) oxidase and myeloperoxidase and up-regulate the activity of antioxidant enzymes such as catalase and paraoxonase. They reduce endothelial dysfunction mainly by their ability to enhance endothelial nitric oxide bioavailability, which is achieved by several mechanisms. The antioxidant properties of statins extend to organ protection especially the myocardium and the lungs.     

Analysis of antihypertensive effects of statins

Hypertension and hyperlipidemia, two powerful risk factors of cardiovascular disease (CVD), often coexist. Therefore, treatment should consider the beneficial properties of drugs used to treat either condition. Statins, the mainstay of lipid-lowering therapy, result in a significant clinical benefit both in primary and secondary CVD prevention. In addition to their hypolipidemic capacity, other properties may contribute to statin-induced benefits. Clinical and experimental evidence indicates that statins may modulate blood pressure (BP). The mechanisms by which statins reduce BP seem to be largely independent of their lipid effects. Although small, reductions in BP are possibly clinically relevant. Large landmark studies confirm that statins can reduce CVD risk in hypertensive patients. These findings suggest that statins could be prescribed as an adjunct in treating hypertension with dyslipidemia or even in patients with “normal” cholesterol levels. Whether the effect of statins on BP is accompanied by an additional decrease in clinical outcomes needs to be investigated in long-term, large-scale trials.     

他汀类药物多效性研究新看点

他汀类药物即羟甲基戊二酰辅酶A(HMG-COA)还原酶抑制剂作为调脂药物在心脑血管疾病中的地位已不可撼动。在过去的近三十年大型的临床注册试验及随机对照试验中,人们对他汀类药物的认识已经有了重大的进步。然而,他汀类药物除调脂作用外,其他具有重要临床意义的作用也逐渐被认识。本文我们将讨论他汀类药物的多效性看点如下。     

Differential metabolic effects of distinct statins

Reciprocal relationships between endothelial dysfunction and insulin resistance suggest that therapies improving endothelial dysfunction will simultaneously improve insulin sensitivity and other metabolic parameters. However, previous studies with some statins either did not alter insulin sensitivity or promoted insulin resistance despite significant improvements in endothelial dysfunction and decreases in circulating pro-inflammatory markers. This may be due to pleiotropic or off-target effects of some statins to cause insulin resistance by diverse mechanisms unrelated to endothelial dysfunction. Indeed, there is evidence of other differential metabolic actions of distinct statins including effects on hydroxymethylglutaryl-CoA reductase inhibition, isoprotenoid synthesis, calcium release, glucose transport, insulin secretion, and/or insulin resistance. Pravastatin increases expression of adiponectin mRNA, enhances adiponectin secretion, increases plasma levels of adiponectin, and enhances insulin sensitivity in mice and humans. Clinical studies including large scale randomized controlled trials demonstrate potential differences between individual statins, with pravastatin promoting risk reduction for new onset of diabetes. Conversely, other statins including atorvastatin, rosuvastatin, and simvastatin all promote significant increase in this risk. Given the frequent concordance of metabolic diseases including diabetes, obesity, and metabolic syndrome with cardiovascular diseases associated with hyperlipidemia, it is important to understand the potential metabolic risks and benefits of therapies with distinct statins. In this review, we discuss these differential effects of statins on metabolic homeostasis and insulin sensitivity.