他汀类药物独立于降脂作用以外的多效性评价

近10多年来,应用他汀类药物预防冠心病的一级、二级试验取得了举世瞩目的成就,肯定了其调脂治疗的益处;同时,他汀类药物调脂以外的作用也备受关注.从临床研究到基础研究,越来越多的证据显示他汀类药物治疗的多效性.这种多效性包括：抑制平滑肌细胞增殖,促进新生血管形成,改善内皮功能,抑制血小板聚集,抑制炎症反应,稳定斑快,降低胰岛素抵抗和骨质吸收.     

他汀类药物的多效性——非调脂治疗作用及临床研究进展

他汀类药物在治疗高胆固醇血症、心脑血管病方面发挥了重要作用,近年来他汀类药物的非调脂作用,即他汀类药物的多效性逐渐受到关注,逐渐增加的临床试验结果显示他汀类药物在心力衰竭、高血压、肾脏保护、延缓退行性瓣膜病进展、抗心律失常、影响凝血系统及促进干细胞分化等方面有重要作用,合理应用可充分发挥他汀类药物疗效,对心血管疾病的治疗可能有重要意义.目前正在进行的有关临床试验研究将逐步阐明他汀类药物多效性机理.     

他汀类药物多效性研究进展

他汀类药物为3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂,临床用于降低胆固醇.随着人们对他汀类药物的深入研究,他汀类药物呈现出令人鼓舞的多效性,包括提高一氧化氮生物利用度、修复受损内皮、抗炎、抗氧化、促新生血管生成、稳定动脉粥样硬化(AS)斑块、动员内皮祖细胞、抑制心肌肥厚,抗心律失常~([1])等.他汀类药物的多效性作用机制可能与其降脂作用互不关联.因为人们观察到,在降脂作用尚未显现时,他汀类的多效性作用已经发生~([2]).目前他汀类药物的多效性已成为心血管领域争论和探索的热点,引起了临床医师及科研工作者的广泛关注.     

他汀类药物多效性的研究进展

他汀类药物在临床上广泛应用,在治疗心血管疾病和肾脏疾病方面取得了很好的效果,为患者解决了很多实际问题,成为患者的福音。这源于这类药物具有较好的药理作用和较少的不良反应。该类药物除了强调脂的药理作用外,还包括调脂以外的药理作用,称之为多效性,其多效性包括改善炎症反应;改善血管的内皮细胞功能;抗血小板聚集和抑制血栓形成;抑制血管平滑肌细胞增殖;保护肾脏等。目前已投入临床使用的该类药物较多,包括阿托伐他汀、辛伐他汀、普伐他汀、氟伐他汀等。现就该类药物的多效性研究进展综述如下。     

他汀类药物和小G蛋白及心肌细胞肥大的关系

他汀类药物具有调脂以外的心血管保护作用,越来越多的实验和临床研究显示,他汀类药物的多效性很大程度上和其抑制小G蛋白的活性有关。现主要从他汀类药物影响小G蛋白信号通路方面,阐述其抑制心肌细胞肥大的主要机制。     

他汀类药物的多效性在心血管疾病中的应用进展

他汀类药物不仅作为羟甲基戊二酰辅酶A还原酶抑制剂降低血清胆固醇水平,还通过改善血管内皮功能、抑制炎症及氧化反应、抗血小板聚集和抑制血栓形成、稳定粥样硬化斑块、抑制心肌重塑及心肌细胞凋亡、抑制心脏电生理重塑及调节心脏植物神经功能等其它多效性在冠状动脉粥样硬化性心脏病、心功能衰竭、心律失常等心血管损伤中发挥其作用。     

他汀类药物多效性及在心力衰竭中的应用

他汀类药物除降脂作用外,还有多效的非调脂作用。近年来很多基础和临床研究都表明他汀类药物多效性对心力衰竭的防治有益。本文就他汀类药物多效性在心力衰竭中的临床应用作一综述。     

他汀类药物治疗后,低密度脂蛋白胞外囊泡中凝血蛋白水平发生改变

正他汀类药物被认为具有多效性,除了降低低密度脂蛋白(low-density lipoprotein,LDL)水平外,还具有抗凝作用。血浆细胞外囊泡(extracellular vesicles,EVs)是涉及凝血等各种生物过程的双层膜囊泡。由于在LDL血浆中的EVs(LDL-EVs)组分与凝血酶活性相关,研究人员假设他汀类药物治疗后LDL-EVs的变化可能与血清凝血蛋白水平变化有所不同,可以提供他汀类药物对凝血功能影响的依据。该研究纳入     

他汀类药物的多效性作用在抗动脉粥样硬化机制中的研究进展

他汀类药物除具有显著的降脂作用外,还具有改善血管内皮功能、抗氧化应激、抗炎、抗血栓及稳定易损斑块等作用,这些除降脂以外的其他作用称之为他汀类药物的多效性作用。本文就他汀类药物的多效性作用在抗动脉粥样硬化机制中的研究进展作一综述。     

他汀类药物的多效性作用及其临床意义

他汀类药物(statins)即3-羟基3-甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂可明显降低心血管事件的发生率和死亡率,是目前临床上应用最广的降胆固醇药物.近年大量实验及临床研究资料显示,他汀类药物除具有显著的降血脂作用外,还有独立于降脂外的作用即多效性,在心血管领域,其多效性主要包括改善血管内皮功能、抑制炎症、抑制平滑肌细胞的增生和促进凋亡、抑制血栓形成和稳定斑块等.然而这些多效性作用在临床治疗中是否具有实际临床获益尚不十分清楚.     

Pleiotropic effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors: candidate mechanisms for anti-lipid deposition in blood vessels

The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are considered first-line therapeutic agents for the prevention of coronary heart disease and atherosclerotic disorders related to hypercholesterolemia. Statins inhibit lipid deposition in the aortic endothelium. Although it has been accepted that the statins are potent inhibitors of cholesterol biosynthesis in the liver and that they lower circulating cholesterol levels, several cholesterol-independent (pleiotropic) effects have been reported. The cholesterol-independent effects of statins involve normalization of the nitric oxide (NO)-NO synthase system, anti-inflammatory effects through the inhibition of cytokine/chemokine production, inhibition of vascular smooth muscle cell proliferation and migration, and inhibition of platelet thrombus formation/reduction of the thrombotic response. Some pleiotropic effects of statins may depend on the inhibition of the biosynthesis of farnesyl- and geranylgeranyl-nonsterol compounds from mevalonate in the cells. The Rho/Rho kinase pathway and the phospatidylinositol-3 kinase/Akt pathway mediate the pleiotropic effects of statins. As variations occur in absorption, metabolism, and excretion mechanisms due to the characteristics of specific statins including their hydrophilicity and lipophilicity, there are differences in the transfer mechanisms of statins into tissues. However, the pleiotropic effects occur regardless of statin hydrophilicity and lipophilicity. This review summarizes the pleiotropic effects of statins on lipid deposition in blood vessels.     

Do pleiotropic effects of statins beyond lipid alterations exist in vivo? What are they and how do they differ between statins?

The inhibition of cellular proliferation, the restoration of endothelial activity, the inhibition of platelet reactivity, and an antioxidant potential are only a few examples of pleiotropic effects of statins. This review analyzes the current knowledge on the pleiotropic properties of this class of drugs and examines the relevant data that support the presence of these effects in vivo. The favorable outcome of major trials of statins has indicated that pleiotropic factors indeed play a role in cardiovascular protection. In addition, recent data indicate that many pleiotropic effects influence mechanisms that belong to the extravascular compartment, as well. Perhaps, some of these properties may eventually justify additional indications for statins and improve the treatment of other diseases, including inflammation and cancer.     

Pathological Changes in Acute Coronary Syndromes: The Role of Statin Therapy in the Modulation of Inflammation,Endothelial Function and Coagulation

Considerable progress has been made in our understanding of the pathophysiology of coronary artery disease (CAD), their acute presentations as acute coronary syndromes (ACS) and the role of LDL cholesterol. In particular there is clear evidence that atherosclerosis is far from being a process that leads to an amorphous flow limiting lesion on an angiogram, but rather involves a complex interplay between the endothelium, inflammatory cells and the coagulation cascade occurring throughout the coronary vascular bed. While a culprit flow limiting lesion may be effectively treated by a drug eluting stent or coronary bypass surgery, this will have little impact on the global molecular processes that determine recurrent plaque instability at non-culprit sites. The search for systemic long term therapy, which is safe and effective and reduces the changes in inflammation, endothelial function and thrombosis that are the hallmark of ACS, has pushed statins to the forefront. A number of recent clinical trials have shown the benefits of early statin therapy in the treatment of ACS. In addition to their effects on LDL cholesterol, statins have a number of properties collectively referred to as pleiotropic effects, which enable them to modulate the adverse biological changes that are associated with ACS. The purpose of this review is to acquaint the reader with the biological changes that accompany ACS, highlight how these pathways may be modulated for clinical benefit by statins and identify potential novel targets for future therapy.Abbreviated abstract. Acute coronary syndromes are associated with pathological changes in inflammation, endothelial function, and coagulation, and many of these are attenuate by statins in a lipid independent manner. In light of recent clinical trials showing the early benefit of statin therapy in ACS, this review discusses how the pleiotropic effects of statins may result in early clinical benefit.     

他汀类药物改善内皮功能的多效应研究进展

内皮功能障碍是动脉粥样硬化开始和进展的重要病理变化之一,他汀类药物能够改善血管内皮功能,除与其降低胆固醇作用外,还体现了许多其它非调脂作用的多种效应,主要包括:调节一氧化氮合酶;抗炎、抗氧化作用;抗白细胞黏附作用;促进动脉损伤后的再内皮化等。一些新的作用靶标,如抑制3-甲基-3,5二羟基戊酸-焦磷酸糖牛儿酯通路、Rho-GTP酶等尤其值得关注。     

Vascular pleiotropy of statins: Clinical evidence and biochemical mechanisms

The ability of statins to lower serum cholesterol and reduce coronary heart disease endpoints has confirmed portions of the lipid hypothesis. However, the time to benefit and increased benefit in overlapping populations have suggested that nonlipid or pleiotropic effects of statins may be present. The apparent benefit of statins in cerebrovascular disease may imply a similar final common pathway among the diverse mechanisms of vascular diseases. Statins’ inhibition of isoprenoid intermediates may modify GTP binding proteins such as Rho. The augmentation of collateral blood flow downstream of activated plaque through endothelial cell nitric oxide synthase may be the biochemical basis of statins’ vascular pleiotropy. Eventual clinical paradigms of statin use may include higher doses to enhance pleiotropic effects and treatment, even when lipid markers are within guidelines.     

Statins and osteoporosis

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, statins are potent inhibitors of cholesterol biosynthesis. Cholesterol-lowering therapy using statins significantly reduces the risk of coronary heart disease. Furthermore, wider use of statins leads to increases of other beneficial effects, so-called pleiotropic effects. These include reductions in cytotoxicity and inflammation reaction, oncoprotective effects - apoptosis of some types of cancer cells, improvement of endothel function, inhibition of thromb formation, decrease of the risk of dementia independent of improvement in the lipid spectrum, inibition of smooth muscle cells proliferation and inhibition of thrombocyte aggregation. One of the important effects is its influence on bone metabolism. Statins augment the expression of bone morphogenetic protein-2, a potent stimulator of osteoblast differentiation and its activity, and promote mineralization by cultured osteoblasts, indicating that statins have an anabolic effect on bone. The author has attempted to summarize the most recent theories on the mechanism of this effect and summarises studies that have been carried out, albeit with inconsistent results.     

Pleiotropic effects of statins in atherosclerosis: role on endothelial function, inflammation and immunomodulation

Atherosclerosis and its complications still represent the major cause of death in developed countries. Statins have been described as the most potent class of drugs to reduce serum cholesterol levels. The effectiveness and rapidity of statin-induced decreases in coronary events led to the speculation that statins possess also cholesterol-independent effects. By the inhibition of 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme crucial to cholesterol synthesis, statins reduce not only cholesterol but also non steroidal isoprenoid intermediates production. Since these isoprenoids, such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate, regulate the small signaling proteins, Ras and Rho, inhibition of these prenylated proteins by statins might account for their non-lipid-related effects. In this review, we describe the numerous beneficial pleiotropic effects of statins that could modulate atherogenesis.     

Pleiotropic Effects of Statins: The Role of Eicosanoid Production

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have potent anti-inflammatory, vasodilatory and anti-platelet effects that are independent of the lipid-lowering effects. These non–lipid-lowering or pleiotropic effects are dependent on HMG-CoA reductase inhibition in tissues other than the liver. In animal models, high-dose statins upregulate cytosolic phospholipase A₂ and cyclooxygenase-2, leading to increased production of prostacyclin and 15-deoxy-PGJ₂. In addition, statins activate protein kinase A, which phosphorylates 5-lipoxygenase, resulting in decreased production of the pro-inflammatory leukotrienes and increased production of 15-epi-lipoxin A4, an eicosanoid with potent anti-inflammatory and inflammation-resolution properties. It is unclear, however, whether these effects occur in the clinical setting and whether these effects (partially) explain the anti-inflammatory effects of statins in patients.     

Direct effects of statins on cells primarily involved in atherosclerosis.

Statins are lipid-lowering agents which act by inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme is responsible for the conversion of HMG-CoA to mevalonate. Products of mevalonate metabolism are critical for several cellular processes of eukaryotic cells, and inhibition of the mevalonate pathway by statins has pleiotropic effects. It has been reported that statins inhibit the migration and proliferation of vascular smooth cells (VSMCs) and macrophages, decrease interleukin-6 and inducible nitric oxide synthase expression in VSMCs, improve endothelial function and up-regulate endothelial nitric oxide synthase expression. The above effects of statins are independent of plasma cholesterol levels, and are completely blocked by exogenous mevalonate and some isoprenoids. These findings suggest that, in addition to their effects on plasma lipids, statins exert direct antiatherosclerotic effects on the cells primarily involved in atherosclerosis.     

Do the pleiotropic effects of statins have a clinical significance?

The effectiveness of statins in the treatment of hypercholesterolaemia and the reduction in cardiovascular risk have now been clearly demonstrated. While their beneficial effects on the reduction of atherosclerosis and its clinical manifestations occur mainly due to the reduction in LDL-cholesterol, some pleiotropic actions which are independent of LDL-cholesterol have frequently been put forward in recent years. In effect, an improvement in endothelial function (increased vasodilatation in particular), an in vitro reduction in smooth muscle cell proliferation, a reduction in thrombosis, promotion of fibrinolysis and positive effects on atheromatous plaque stabilisation have been observed. Elsewhere, some anti-oxidant and anti-inflammatory properties have been attributed to statins. However, many of the described 'pleiotropic' effects are not due to the direct action of statins, but occur with the reduction in LDL-cholesterol. Furthermore, certain in vitro effects only occur at much higher than therapeutic doses. These considerations have therefore caused doubt about the clinical significance of the statins' pleiotropic effects. Finally, analysis of the results of human clinical trials on statins have proved that their effectiveness relies on the reduction in LDL-cholesterol and that the pleiotropic effects do not actually have a clinical implication.