他汀类药物对血管新生作用及机制的研究

小剂量他汀类药物能促进骨髓来源内皮祖细胞的动员和分化,提高内皮祖细胞的数量和分化、迁移能力,促进缺血组织血管新生。小剂量他汀类药物可能通过磷脂酰肌醇-3激酶(PI-3K)／苏氨酸激酶(Akt)旁路增加内皮型一氧化氮合酶的表达,从而动员内皮祖细胞。而大剂量他汀类药物可抑制血管新生。     

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。     

他汀类药物预处理时间对兔心肌缺血再灌注损伤的影响

目的 观察普伐他汀、阿伐他汀和氟伐他汀一次性预处理的时间对兔心肌缺血再灌注损伤的影响及其机制.方法 选择日本大耳白兔70只,分别为普伐他汀、阿伐他汀和氟伐他汀组,每组21只,药物各组又分三个小组,对照组7只.实验前5d、3d和2h通过灌胃一次性分别给予普伐他汀、阿伐他汀和氟伐他汀10 mg/kg,随后制作心肌梗死模型,术后测量心肌梗死面积并检测缺血区内皮型一氧化氮合酶（eNOS）活性.体外实验部分培养人脐静脉内皮细胞（HUVECs）,观察以上他汀类药物作用0 min、5 min、15 min、20 min和30 min后诱导HUVECs表达eNOS的变化,通过Westernblot检测信号分子p-Akt（磷酸化丝/苏氨酸蛋白激酶）的含量.结果 提前2h给药能显著减少各组心肌缺血再灌注后的心肌梗死面积,增加缺血区eNOS的含量.缺血前5d和3d给药对心肌损伤改善不显著.细胞实验发现,以上他汀类药物20 min内即能上调血管内皮细胞eNOS表达,同时p-Akt的含量增加.结论 短时间内一次性预处理应用他汀类药物能够减轻缺血再灌注损伤.其机制可能与他汀类药物上调p-Akt信号分子,在短时间内诱导血管内皮细胞eNOS表达有关.     

他汀类药物与血管内皮功能

他汀类药物是一类可有效降低低密度脂蛋白胆固醇 (LDL C)的药物 ,近年来 ,一些研究显示他汀类药物还具有不依赖于调脂作用的有益功效 ,明显降低了心血管病事件发病率和病死率。血管内皮细胞的功能损害已被认为是动脉粥样硬化发生、发展过程中一个重要的指标 ,故他汀类药物对血管内皮细胞功能的影响尤为人们所重视。本文就近年来血管内皮功能本身的研究进展及他汀类药物对内皮功能影响的研究近况作一综述。     

他汀类药物的非降脂作用与血管重构

大规模研究证实，他汀类药物不仅有降脂作用，而且有重要的非降脂作用和直接血管效应，强化降脂治疗能减少急性冠脉综合征（ACS）、高血压和老年人群等高危心血管事件的发生率。心血管事件的共同病理基础是血管重构（VR），各种致病因子多通过影响血管功能和结构而引起临床心血管事件。研究显示，他汀类药物能减轻和逆转VR。为了解他汀类药物的非降脂及其逆转VR作用，本文结合文献对其综述如下。     

内皮祖细胞对血管新生的影响及他汀的干预作用

他汀类药物作为传统降血脂药物,其降脂外作用逐渐受到重视,尤其在保护血管内皮功能促进血管新生方面。血管内皮祖细胞作为血管内皮前体细胞,参与出生后血管新生过程,促进血管内皮修复。本文就他汀类药物对血管内皮祖细胞及血管新生影响的研究进展做一综述     

他汀类药物对血管及血栓形成的作用

他汀类的非调脂作用有抗炎作用．抑制血管平滑肌细胞增殖、血小板功能，改善咀管内皮功能等的作用。     

他汀类药物对血管重构的干预机制

他汀类药物对血管重构具有干预作用,本文就其干预机制作一综述。     

匹他伐他汀促进小鼠血管新生作用及其机制的研究

目的探讨匹他伐他汀对小鼠血管新生的促进作用及其可能的作用机制。方法建立野生型C3H／He小鼠下肢缺血模型并分为2组,缺血对照组,匹他伐他汀组。使用激光多普勒血流测定仪测定实验小鼠投药前、下肢缺血手术后双下肢血流。免疫荧光组化sP法计数缺血肢毛细血管数。免疫酶组化直接法计数缺血肢磷酸化蛋白激酶Akt（p-Akt）阳性细胞数。蛋白印迹杂交方法检测缺血肢血管内皮生长因子蛋白表达。镉还原Griess法测定实验结束后血清一氧化氮代谢产物含量。结果匹他伐他汀使实验小鼠术后缺血肢血流恢复明显,缺血肢与非缺血肢血流面积比明显增加;缺血肢毛细血管密度明显增加、p-Akt活性增加（p-Akt阳性细胞数明显增加）;血中一氧化氮代谢产物含量明显增高;缺血肢血管内皮生长因子蛋白表达增强。结论匹他伐他汀有促进小鼠血管新生的作用。     

他汀类药物治疗肺动脉高压作用机制的研究进展

他汀类药物是目前治疗高胆固醇血症的首选药物,临床已广泛应用于血脂异常的治疗。近年来发现他汀类药物具有多种独立于降脂作用外的其它作用,有实验表明可降低肺动脉高压,其机制可能为抑制细胞增殖、诱导细胞凋亡、改善血管内皮功能、抗炎等。     

The genetics of statin-induced myopathy

Objective

Our goal was to use genetic variants to identify factors contributing to the muscular side effects of statins.

Background

Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are usually well tolerated medications, but muscle symptoms, ranging from mild myalgia to clinically important rhabdomyolysis are an important side effect of these drugs and a leading cause of noncompliance. Recent results suggest that genetic factors increase the risk of statin-related muscle complaints. We performed a systematic review of the medical literature to determine genetic factors associated with statin myopathy.

Methods

We identified English language articles relating statin myopathy and genetic diseases and gene variants via a PubMed search. Articles pertinent to the topic were reviewed in detail.

Results/Conclusions

Our review suggests that some patients are susceptible to statin myopathy because of pre-existing subclinical inherited muscular disorders, or genetic variation in statin uptake proteins encoded by SLCO1B1 or the cytochrome P enzyme system. Variations in genes affecting pain perception and polymorphism in vascular receptors may also contribute to statin myopathy. None of the variants identified in this review suggested novel metabolic mechanisms leading to statin myopathy.     

Clinical perspectives of statin-induced rhabdomyolysis

Fear of muscle toxicity remains a major reason that patients with hyperlipidemia are undertreated. Recent evaluations of statin-induced rhabdomyolysis offer new insights on the clinical management of both muscle symptoms and hyperlipidemia after rhabdomyolysis. The incidence of statin-induced rhabdomyolysis is higher in practice than in controlled trials in which high-risk subjects are excluded. Accepted risks include age; renal, hepatic, and thyroid dysfunction; and hypertriglyceridemia. New findings suggest that exercise, Asian race, and perioperative status also may increase the risk of statin muscle toxicity. The proposed causes and the relationship of drug levels to statin rhabdomyolysis are briefly reviewed along with the problems with the pharmacokinetic theory. Data suggesting that patients with certain metabolic abnormalities are predisposed to statin rhabdomyolysis are presented. The evaluation and treatment of patients’ muscle symptoms and hyperlipidemia after statin rhabdomyolysis are presented. Patients whose symptoms are related to other disorders need to be identified. Lipid management of those whose symptoms are statin-related is reviewed including treatment suggestions.     

Current overview of statin-induced myopathy

Statins are an efficacious and well-tolerated class of lipid-altering agents that have been shown to reduce the risk of initial and recurrent cardiovascular events. However, cerivastatin was withdrawn from the world market because of its potential for severe myotoxic effects. Since the benefits of statin treatment outweigh the small risk of adverse events, statins remain the first-line therapy for lipid lowering and preventing atherosclerotic cardiovascular diseases. The risk of myopathy may be minimized with the appropriate choice of agent and by identifying patients at risk of myotoxic effects. Elderly or female patients, or those with concomitant medications or impaired metabolic processes, may be at increased risk and should be monitored closely. The risk of myopathy may also be inferred from the pharmacologic and pharmacokinetic properties of the statin used. Since myotoxic events are more frequent at higher doses, statins that are effective in reducing cholesterol levels and helping patients to reach target levels at start doses may be useful. The lipophilicity of a statin and its potential for drug-drug interactions may also help to determine the likelihood of muscular effects. Drug-drug interactions may be avoided by selecting a statin that does not share the same metabolic pathway.     

Mechanism and its regulation of tumor－induced angiogenesis

Tumor angiogenesis is the proliferation of a network of blood vessels that penetrates into cancerous growths, supplying nutrients and oxygen and removing waste products. The process of angiogenesis plays an important role in many physiological and pathological conditions. Solid tumors depend on angiogenesis for growth and metastasis in a hostile environment. In the prevascular phase, the tumor is rarely larger than 2 to 3 mm^3 and may contain a million or more cells. Up to this size, tumor cells can obtain the necessary oxygen and nutrient supplies required for growth and survival by simple passive diffusion. The properties of tumors to release and induce several angiogenic and antiangiogenic factors which play crucial roles in regulating endothelial cell (EC) proliferation, migration, apoptosis or survival, cell-cell and cell-matrix adhesion through different intracellular signalinq are thought to be the essential mechanisms during tumor-induced angiogenesis. Tumor angiogenesis actually starts with tumor cells releasing molecules that send signals to surrounding normal host tissue. This signaling activates certain genes in the host tissue that, in turn, make proteins to encourage growth of new blood vessels. In this review, we focus the mechanisms of tumor-induced angiogenesis, with an emphasis on the regulatory role of several angiogenic and anti-angiogenic agents during the angiogenic process in tumors. Advances in understanding the mechanisms of tumor angiogenesis have led to the development of several most effective anti-angiogenic and anti-metastatic therapeutic agents and also have provided several techniques for the regulation of cancer′s angiogenic switch. The suggestion is made that standard cytotoxic chemotherapy and angiogenesis inhibitors used in combination may produce complementary therapeutic benefits in the treatment of cancer.     

他汀类降脂药致肝损害的诊断研究进展

他汀类降脂药是一类选择性3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂,也是目前临床上应用广泛的降低血脂进而减少心血管事件发生的药物。服用他汀类药物一段时间后,部分患者可能会出现转氨酶升高、肝脾肿大、黄疸等肝功能损害的临床表现,也可仅仅表现为无症状的转氨酶升高、直接胆红素升高、凝血酶原时间延长等。他汀类药物致肝损害(SILI)的诊断很大程度依靠临床医师经验,容易漏诊,因此本文对国内外SILI诊断进行了总结,以供临床医师参考,提高诊断水平。