Novel concepts of statin therapy for cardiovascular risk reduction in hypertension

Hypertension is associated with an increase in cardiovascular events. Pathophysiological mechanisms of this include endothelial damage/dysfunction, inflammatory activation, insulin resistance, platelet activation and alterations in the coagulation cascade leading to a prothrombotic state. Dyslipidaemia acts synergistically with hypertension in increasing cardiovascular risk. HMG CoA reductase inhibitors (statins) are lipid-lowering drugs and more recently have been shown to have a significant pleiotropic effect on endothelial function, inflammation, platelet activation and coagulation. Statins affect the whole pathophysiology of atherogenesis from deposition to plaque rupture and thrombogenesis because of its pleiotropic effects. Therefore it is intuitive that statins may be of benefit in hypertensive patients with conventionally normal lipid levels by preventing the pathological effects of hypertension. There is an increasing clinical evidence base for statins use in patients with hypertension. In this article, the novel pleiotropic and conventional mechanisms of statins, and clinical data of statin therapy in patients with hypertension are reviewed.     

Endothelial dysfunction, oxidative stress and inflammation in atherosclerosis: beneficial effects of statins

Atherosclerosis and its complications represent the major cause of death in developed countries. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A [HMGCoA] reductase and consequently inhibitors of cholesterol biosynthesis. Statins have been described as the most potent class of drugs to reduce serum cholesterol levels. In clinical trials, statins are beneficial in primary and secondary prevention of coronary heart disease. Statins, were initially designed as cholesterol-lowering drugs. However, these drugs, besides their lipid-lowering properties, exert a number of protective effects on the cardiovascular system that emerged over the past years. The benefits observed with statin treatment appear to be greater than that might be expected from reduction in lipid levels alone, suggesting effects beyond cholesterol lowering. These cholesterol-independent effects have been called "pleiotropic". The cholesterol-independent or "pleiotropic" effects of statins involve improvement of endothelial function, stability of atherosclerotic plaques, decrease of oxidative stress and inflammation, and inhibition of thrombogenic response. These pleiotropic effects of statins have been proposed as key properties of these drugs to reduce cardiovascular morbidity and mortality. The present review will emphasize the molecular mechanisms underlying the effects of statins on endothelial function and oxidative stress. In particular, inhibition of small GTP-binding proteins, Rho, Ras and Rac, which are regulated by isoprenoids [farnesyl pyrophosphate and geranylgeranyl pyrophosphate], seems to play an important role in mediating the pleiotropic effects of statins.     

Statins for diabetic cardiovascular complications

The prevalence of diabetes mellitus (DM), particularly Type 2 DM, has rapidly increased in industrialized and many developing countries. The predominant cause of death in diabetic patients is vascular complications. Dyslipidemia and hypercholesterolemia are common in diabetic patients. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) were designed for lowering cholesterol synthesis. Landmark clinical trials indicated that statins effectively reduced cardiac death and events in patients with coronary artery disease or DM. The benefits of statins on the prevention of vascular events were independent from age, sex or baseline lipid levels in diabetic patients. Statins not only prevent atherosclerotic macrovascular complications, but also postpone the development of microvascular complications of DM, such as nephropathy and retinopathy. The non-cholesterol lowering or pleiotropic effects of statins have attracted vast attention. Results from experimental and clinical studies suggest that statins may attenuate inflammation, oxidative stress, coagulation, platelet aggregation, and improve insulin resistance, fibrinolysis and endothelial functions and help to prevent thrombosis, restenosis or organ transplantation rejection. Statins may affect the intracellular prenylation of proteins, which modulate the activity of small-GTP binding proteins. This may be an underlying mechanism for some pleiotropic effects of statins. Statins have an excellent safety profile and seldom cause adverse effects. Increasing evidence suggests that statins are the current treatment of choice to prevent vascular complications in diabetic patients with hypercholesterolemia.     

他汀类药物多效药理作用及其机制研究进展

他汀类是临床上治疗高胆固醇血症主要药物, 广泛应用于冠心病一级及二级预防。近年来研究表明,他汀类药物还具有降脂外的多重作用,包括改善血管内皮功能、抗炎症、抗氧化作用、稳定动脉粥样硬化和抗肿瘤作用等。本文围绕他汀类药物对血管疾病和肿瘤的作用及机制展开综述。     

Benefits of statins in cerebrovascular disease

Although elevated cholesterol levels have been associated with coronary heart disease, the evidence for a role of cholesterol in stroke is less well defined. Epidemiological studies indicate that high lipid levels are linked with an increase in ischemic stroke, while low lipid levels may increase the risk of hemorrhagic stroke. Lipid lowering with statins reduces the incidence of ischemic stroke without increasing the frequency of hemorrhagic stroke. The benefits of statins on stroke may be due to a combination of mechanisms. Statins lower cholesterol levels and reduce the progression of atherosclerotic plaque formation in carotid arteries, and the incidence of emboli from cardiac, aortic and carotid sites. Furthermore, statins may produce cholesterol-independent effects such as improving cerebral blood flow and reducing inflammation and oxidative stress, which could limit the size of an ischemic lesion. Statins offer potential benefits for reducing the incidence and improving the prognosis of stroke.     

Telomere/Telomerase system: a new target of statins pleiotropic effect?

Statins are well established drugs for primary and secondary prevention of coronary artery disease (CAD). Despite the well-known ability of statins to lower cholesterol, it is now clear that clinical benefits are also substantially higher than expected and several clinical trials, like JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin trial) have indicated that such clinical effects are independent of cholesterol reduction. These cholesterol-independent actions have been named "pleiotropic effects" and include: anti-oxidation and anti-inflammatory effects, modulation of immune activation, stabilization of atherosclerotic plaque, decreased platelet activation, inhibition of cardiac hypertrophy, reduction of cytokine-mediated vascular smooth muscle cell (VSMC) proliferation and improvement of endothelial function. Recently, additional pleiotropic effects of statins on "cellular senescence" have been seen in different cell types, including endothelial progenitor cells (EPC), endothelial cells (EC), VSMC and chondrocytes. At the molecular level, the effect of statins on cellular senescence could be mediated by their interaction with the telomere/telomerase system. Recent evidence suggests that the anti-aging effects of statins are linked to their ability to inhibit telomere shortening by reducing either directly and indirectly oxidative telomeric DNA damage, as well as by a telomere capping proteins dependent mechanism. In this review, we discuss the pleiotropic effects of statins, focusing on the telomere/telomerase system. We will also present our current findings regarding leukocyte telomere length in very old people with myocardial infarction on statin therapy.     

基于AMPK及下游靶点的黄连素防治缺血性脑卒中的研究进展

从近些年的研究可知,能量代谢障碍是造成缺血性脑损伤重要的始动因素,继而出现氧化应激、神经炎症、谷氨酸受体的激活、钙超载、凋亡等病理事件的发生。实验性及临床研究发现黄连素可以治疗缺血性脑卒中,其可能机制在于激活腺苷酸活化蛋白激酶及其下游靶点,包括核因子相关因子-2,核因子-κB,磷酸肌醇3-激酶/蛋白激酶B和雷帕霉素靶蛋白,从而改善氧化应激、神经炎症、谷氨酸兴奋性毒性、凋亡,促进自噬和血管生成等,为黄连素防治缺血性脑卒中的临床应用提供有力依据。     

热休克蛋白70对缺血性脑卒中的保护作用

热休克蛋白70（heat shock protein 70, Hsp70）是生物体产生的一种可增强细胞对损伤的耐受程度、维持细胞正常代谢功能并提高细胞生存率的高度保守的应激蛋白。本文回顾了近几年有关Hsp70与缺血性脑卒中相关的报道,发现Hsp70可能通过提高细胞抗氧化应激能力、抑制炎症反应以及抑制细胞凋亡,在缺血性脑卒中发挥保护作用。本文对Hsp70在缺血性脑卒中进程中的保护作用及其机制进行了概述。     

Statins and the endothelium

Statins have been shown to have pleiotropic effects apart from serum lipid-lowering effect in human. One of the major target organs for the effects of statins is the vascular endothelium, which plays an important role in the development of atherosclerosis and angiogenesis. Recent numerous studies have shown that the statins' cholesterol-independent vascular effects appear to involve directly restoring or improving endothelial function by increasing NO production, promoting re-endothelialization after arterial injury, and inhibiting inflammatory responses within the vessel wall that are thought to contribute to atherosclerosis. This review provides an update of the unique effects of statins on endothelial cells including endothelial progenitor cells as well as highlighting the therapeutic potential of statins beyond their established lipid-lowering effects.     

Atorvastatin and statins in the treatment of heart failure

Heart failure (HF) affects approximately five million people in the US and survival at 5 years is only 50% despite advances in medical and device therapy. Statins are of novel therapy for these patients, which may be beneficial in both ischemic and non-ischemic HF. In addition to lipid-lowering and anti-atherosclerotic effects, statins demonstrate many non-lipid or pleiotropic effects that could be beneficial in HF. They may inhibit or reverse myocardial remodeling, inhibit inflammation in HF, improve endothelial function and restore autonomic nervous system balance. Numerous observational studies of HF cohorts have linked statin therapy with significantly improved survival. Small prospective clinical studies of atorvastatin and simvastatin in systolic HF are promising, documenting improved ventricular systolic function and decreased inflammatory biomarkers with statin therapy. Definitive recommendations regarding statin therapy in all HF must await the completion of large scale outcome trials of statins in non-ischemic HF.     

Atorvastatin and statins in the treatment of heart failure

Heart failure (HF) affects approximately five million people in the US and survival at 5 years is only 50% despite advances in medical and device therapy. Statins are of novel therapy for these patients, which may be beneficial in both ischemic and non-ischemic HF. In addition to lipid-lowering and anti-atherosclerotic effects, statins demonstrate many non-lipid or pleiotropic effects that could be beneficial in HF. They may inhibit or reverse myocardial remodeling, inhibit inflammation in HF, improve endothelial function and restore autonomic nervous system balance. Numerous observational studies of HF cohorts have linked statin therapy with significantly improved survival. Small prospective clinical studies of atorvastatin and simvastatin in systolic HF are promising, documenting improved ventricular systolic function and decreased inflammatory biomarkers with statin therapy. Definitive recommendations regarding statin therapy in all HF must await the completion of large scale outcome trials of statins in non-ischemic HF.     

Modulation of the inflammatory process by statins

Statins reduce cholesterol levels through competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme that regulates cholesterol synthesis. The cholesterol-lowering effect of statins is also due to an increase in the uptake of cholesterol by cells as a result of intracellular cholesterol depletion and enhanced expression of low-density lipoprotein (LDL) receptors. The use of statins as lipid-lowering agents has lead to remarkable changes in the treatment and prevention of ischemic heart disease. Results of large clinical trials of patients with ischemic heart disease have demonstrated that statins reduce inflammatory markers such as C-reactive protein, an independent risk factor in the disease. Statins exhibit properties that are beyond their lipid-lowering effects. These non-lipid-lowering properties involve the inhibition of the isoprenoid pathway through decreased synthesis of many nonsteroidal isoprenoid compounds. The focus on the immunomodulatory effect of statins is the result of the positive outcome of pravastatin treatment in cardiac transplantation patients, as well as angiographic regression studies showing insignificant changes in the degree of coronary stenosis despite a large reduction in cardiac events. Statin treatment reduces the risk of ischemic stroke despite the fact that LDL cholesterol is not directly associated with the risk of stroke. This observation lead to the investigation of the role of statins in inflammation and the immune system. Recent research data demonstrated that statins inhibit the induction of the major histocompatibility (MHC) class II expression by interferon-gamma (IFN-gamma), leading to repression of MHC II-mediated T-cell activation. Furthermore, statins inhibit the expression of specific cell surface receptors on monocytes, adhesion molecules and also integrin-dependent leucocyte adhesion. While statins may stimulate the secretion of caspase-1, IL-1beta and IL-18 in peripheral mononuclear cells in response to Mycobacterium tuberculosis, they exhibit additional effects on inflammation by decreasing IL-6 synthesis in human vascular smooth muscle cells (VSMC) in vitro. The focus of this monograph is to highlight the role of statins in the modulation of the immune system and inflammatory processes.     

他汀类药物在缺血性卒中及短暂性脑缺血发作二级预防中的作用

目的对他汀类药物在缺血性卒中及短暂性脑缺血发作二级预防中的作用进行评价分析,为今后的临床预防以及合理用药工作提供可靠的参考依据。方法 抽取在2010年1月至2012年12月间本院收治的缺血性卒中/短暂性脑缺血发作患者218例,将其按照病情程度分成高危组、极高危Ⅱ组、极高危Ⅰ组,对这三组患者入院后与随访3个月的临床用药情况进行统计分析。结果本组218例患者中在住院期间预防性应用他汀类药物者115例,应用率为52.75%,其中极高危Ⅰ组他汀类药物应用与指南的符合率较高危组与极高危Ⅱ组高(P<0.05);随访3个月后,他汀类药物应用者为49例,应用率为22.48%,较住院期间发生显著降低(P<0.05)。结论在预防缺血性脑卒中和短暂性脑缺血发作时他汀类药物发挥了重要作用,降低了复发率,然其二级预防中用药依从性较差,与应用指南符合率较低,临床应予以注意,做好预防工作,合理用药,以改善患者预后。     

他汀类药物对脑梗死病人血清中TNF-α及IL-6的影响

随着对脑梗死病人发病机制不断深入的研究,脑缺血后的炎症反应越来越引起人们的重视,而阻断脑缺血后炎症级联反应是改善脑缺血-再灌注损伤的理想策略。他汀类药物临床试验表明,它具有抗氧化、抗炎症、抗兴奋毒性以及抑制血小板聚集和血栓形成等降脂以外的抗缺血性脑损害作用,可大大降低脑梗死的发生率。本文拟从脑梗死病人血清中2个重要的炎性因子肿瘤坏死因子(TNF-α)和白细胞介素6(IL-6)进行论述,以阐明他汀类药物对脑梗死病人炎性因子的影响。     

他汀类药物对非缺血性心力衰竭的有益作用

他汀类药物可能通过抗炎、改善内皮功能、减轻氧化应激与调节神经体液因素等机制产生对慢性心力衰竭的有益作用。对冠心病或心力衰竭研究的回顾性分析显示，他汀类药物可改善慢性心力衰竭患者预后，与是否为缺血性病因无关。现综述近年他汀类药物对非缺血性心力衰竭的作用机制、回顾性分析及前瞻临床研究，结果显示它可改善左室功能与炎症状态，但需要进一步的大规模随机双盲研究验证。     

基于缺血性脑卒中再灌注损伤机制的抗氧化纳米药物研究进展

在缺血性脑卒中-再灌注过程中,活性氧异常增多引起的脑组织神经元氧化应激是脑缺血-再灌注损伤的最主要病理机制。快速恢复脑组织血流灌注,同时抑制神经元氧化损伤是治疗缺血性脑卒中的有效途径。目前抗氧化类药物存在生物利用率低、作用方式单一及副作用大等缺点,极大限制了其疗效与临床应用。近年来,纳米药物因其尺寸、形貌可控及表面可修饰性等优势,在生物应用中展现出良好的应用前景,有望突破缺血性脑卒中神经保护类药物开发的瓶颈。重点阐明脑缺血-再灌注损伤的机制,综述抗氧化纳米药物的设计合成及其逆转神经元氧化损伤的作用机制与应用,为防治缺血性脑卒中提供新的思路。     

他汀类药物抗肿瘤作用机制的研究进展

他汀类药物属于3-羟基-3-甲基戊二酸单酰辅酶A还原酶抑制剂,近年来大量的临床研究显示,他汀类药物也具备抗肿瘤作用。他汀类药物可以通过抑制肿瘤细胞增殖、促进肿瘤细胞凋亡、抑制肿瘤细胞侵袭和迁移、抗肿瘤血管生成、增强抗肿瘤免疫等发挥抗肿瘤作用。因此总结了他汀类药物的抗肿瘤作用机制,期望为他汀类药物进一步应用于肿瘤的治疗提供科学依据和理论支撑。     

Statins in the treatment of acute ischemic stroke

3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (also known as statins) are drugs active in the blockade of cholesterol synthesis and thus lowering cholesterol serum levels. Since their discovery, experimental evidence showed that statins strongly reduced atherogenesis and the risk of acute ischemic complications, such as acute myocardial infarction and stroke. More recently, direct anti-atherosclerotic effects of statins (independently of lipid profile improvement) have been also shown, suggesting new potential applications for these drugs in both primary and secondary prevention of acute cardiovascular events. Despite some controversies exist, the use of statins has been shown to improve both incidence and survival in acute ischemic stroke. The molecular mechanisms underlying statin-mediated clinical benefits were recently identified in the reduction of carotid plaque vulnerability and the increase of neuroprotection. In the present review, we will update evidence on the promising results with statins to improve ischemic stroke outcomes.     

Peripheral arterial disease: a missed opportunity to administer statins so as to reduce cardiac morbidity and mortality

Peripheral arterial disease (PAD) is a common condition associated with an increased risk of coronary heart disease, myocardial infarction and stroke. It follows that PAD merits aggressive preventive treatment that includes lipid lowering drugs (mainly statins). This review summarises the current knowledge concerning the use and mechanisms of action of statins in patients with PAD. Statins not only lower the risk of vascular events, but they also improve the symptoms associated with PAD. There is also evidence that statins reduce surgical mortality and improve graft patency and limb salvage. Because of the high risk, a more aggressive goal [i.e. low density lipoprotein cholesterol (LDL-C) of 70 mg/dl; 1.8 mmol/l] [National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III), revised guidelines 2004] should be considered to maximally reduce the atheroma burden and related events. Not all statins can achieve this LDL-C target. Furthermore, there may be a need to use an additional lipid lowering drug so as to achieve the LDL-C goal and benefit from the different modes of action. Statins exert beneficial pleiotropic effects on haemostasis, the vasculature and inflammatory markers. There is also evidence that statins improve renal function (the plasma creatinine level is considered as an emerging vascular risk factor). Since PAD patients often take several drugs, there is a need to carefully consider their selection so as to maximize benefits and minimize adverse effects. Patients with PAD often do not receive adequate lipid lowering treatment. This situation needs to change.