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.     

所有缺血性卒中患者都应该使用大剂量他汀类药物吗?

他汀类药物治疗已成为缺血性卒中预防的标准方法,而且正在成为急性缺血性卒中的治疗选择.他汀类药物独立于胆固醇之外的多效性作用是将其用于缺血性卒中治疗的主要依据,这些多效性作用可能具有神经保护作用,进而改善患者的神经功能转归.同时,鉴于有研究显示他汀类药物的治疗作用存在剂量依赖性,因此主张采用大剂量他汀治疗.但是,围绕是否应将大剂量他汀类药物应用于不同机制的缺血性卒中患者仍然存在争论.     

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。     

Rho激酶：他汀类药物抗动脉粥样硬化的重要靶点

他汀类药物作为抗动脉粥样硬化的经典药物,其降脂外作用即多效性正受到越来越多的关注.近年研究发现,Rho激酶与他汀类药物多效性密切相关.国外大量研究揭示Rho激酶很有可能成为今后心血管疾病治疗的重要靶点.本文结合最新研究进展,概述Rho激酶的结构及激活机制,探讨其与动脉粥样硬化的关系及他汀类药物抑制Rho激酶活性的循证证据及机制,同时展望Rho激酶抑制剂未来在动脉粥样硬化性疾病预防和治疗中的应用前景.     

他汀类药物能否常规用于治疗慢性心力衰竭?——CORONA解密

循证医学证明,急性心肌梗死早期应用他汀类药物治疗可以获益;小样本试验认为小剂量他汀类药物治疗慢性心力衰竭(CHF)有益,而大剂量治疗没有获益.尽管他汀类药物具有多效性的药理作用,由于CHF患者低TC水平具有不良的预后,应用他汀类药物治疗CHF存在潜在风险[1].他汀类药物能否成为CHF治疗的常规药物,有待循证医学的证据.     

他汀类药物多效性的临床研究进展

近年来数个大规模临床研究相继证实,应用他汀类药物可明显降低血清总胆固醇和低密度脂蛋白胆固醇水平,显著降低冠心病发病率、心血管病死亡率乃至全因死亡率,从而奠定了他汀在冠心病一级、二级预防中的基石地位。然而,随着基础与临床研究的深入,越来越多的证据表明,他汀类药物具有独立于调脂作用外的多种疗效,即他汀的多效性。现将着重从循证医学的角度对他汀类药物的多效性进行综述。     

动脉粥样硬化炎症机制及阿托伐他汀药物多样性的研究进展

近年研究显示,动脉粥样硬化是一种慢性炎症。炎症在动脉粥样硬化的发生、发展和演变过程中起着重要作用。他汀类药物是治疗高脂血症及预防动脉粥样硬化性疾病的基石。已有大量研究证实,他汀类药物通过降脂作用改善心血管疾病的预后,而且还通过抗炎、改善内皮功能、抗血小板活性、稳定斑块等作用使患者获益,即他汀类药物有多效性。现就具有代表性的阿托伐他汀,对他汀类药物多效性的研究进展进行综述。     

冠状动脉粥样硬化斑块消退研究进展

冠状动脉粥样硬化的发生与低密度脂蛋白及炎症反应、内皮功能减退等有关。近年来多项临床试验证实早期强化应用他汀类药物可以通过降低低密度脂蛋白、抗炎、改善内皮功能等途径改善急性冠脉综合征患者的预后。其中他汀类药物发挥的抗炎症反应、改善内皮功能等多效性作用日益受到重视。而应用血管内超声的研究发现强化他汀类治疗能够显著遏制甚至消退冠状动脉粥样斑块。     

The pleiotropic effects of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in cardiovascular disease: a comprehensive review

The hydroxy-methyl-glutaryl-CoA reductase inhibitors (statins) are used extensively in the treatment of hyperlipidemia, and in the long-term prevention of coronary artery disease and stroke. They have also demonstrated a benefit in a variety of other cardiovascular disease processes. These secondary actions are known as pleiotropic effects. An updated discussion on the pleiotropy of statins is provided, and emphasizes the importance of randomized, placebo-controlled trials to further elucidate the potential benefits of these non-lipid-lowering actions in the treatment of cardiovascular disease.     

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.     

冠状动脉粥样硬化性心脏病高危患者的强化降脂与瑞舒伐他汀

瑞舒伐他汀具有独特的临床药理特点,其降脂疗效、安全性、成本-效益比均优于其他他汀类药物,具有降脂疗效以外的＂多效性＂,是冠状动脉粥样硬化性心脏病高危患者强化降脂、减少心血管事件的最佳选择,呼吁瑞舒伐他汀能早日在基层医疗单位普及。     

他汀类与非酒精性脂肪肝病患者的卒中预防

非酒精性脂肪肝病(non-alcoholic fatty liver disease,NAFLD)是慢性肝病中的一个重要类型,其发病率日益增高,是代谢综合征的肝脏表现,与心脑血管病的发生关系密切.对NAFLD患者的卒中预防十分重要.他汀类药物是最重要的一类降胆固醇药物,通过抑制羟甲基戊二酰辅酶A(hydroxy-methyl-glutaryl coenzyme A HMG-CoA)还原酶,减少胆固醇合成,上调肝脏低密度脂蛋白(low-density lipoprotein,LDL)受体,降低循环低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL-C)水平,有效降低卒中风险.此外,他汀类的多效性以及对胆同醇相关细胞信号通路的影响,能减缓或防止NAFLD的进展.由于他汀类药物对肝脏有一定的不良作用,是否能应用于慢性肝病患者存在较大争议.现有证据显示,他汀类药物可在NAFLD患者中安全使用,通常无需监测肝酶,过分关注他汀类药物的肝毒性反而可能采取不恰当的停药,导致心血管事件风险的增高.为此,他汀类对NAFLD患者的有效性及安全性尚需进一步评估.     

Statins and risk of venous thromboembolic diseases: A two-sample mendelian randomization study

Background and aimsIn observational studies, statins have been suggested to have protective effects on venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). To this aim, we performed a two-sample mendelian randomization (MR) analysis to determine whether these associations were causal.Methods and resultsData on the single nucleotide polymorphisms (SNPs) related to statin medication were obtained from the FinnGen study, and data for VTE, PE and DVT of lower extremities (LEDVT) were from the UK Biobank study, respectively. Inverse variance weighted (IVW) method was used as the principal analysis of MR, and sensitivity analysis was performed to detect horizontal pleiotropy and heterogeneity. MR estimates showed an inverse causal association between statin medication and the risk of VTE (odds ratio [OR]: 0.999, 95% CI: 0.998–1.000, P = 0.004), PE (OR: 0.999, 95% CI: 0.999–1.000, P = 0.011) and LEDVT (OR: 0.999, 95% CI: 0.999–1.000, P = 0.008).ConclusionOur findings provide direct evidence that statins might decrease the risk of VTE, PE and LEDVT in agreement with observational studies. The specific mechanism of statin therapy for venous thromboembolism needs to be further studied.     

Antagonistic pleiotropy and the stress theory of aging

The ecological stress theory of aging incorporates the normally harsh environments of natural populations and hence restricted resources. Especially towards lethal extremes, positive associations are expected among fitness traits underlain by selection for energetic efficiency favoring genotypes for stress resistance. Positive pleiotropy is therefore expected for fitness traits across varying ages under these conditions. Furthermore, hormetic zones are regions of maximum energetic efficiency, also implying positive pleiotropy. Negative pleiotropy may therefore be mainly a phenomenon of benign environments.     

From the Cover: Genomic patterns of pleiotropy and the evolution of complexity

Pleiotropy refers to the phenomenon of a single mutation or gene affecting multiple distinct phenotypic traits and has broad implications in many areas of biology. Due to its central importance, pleiotropy has also been extensively modeled, albeit with virtually no empirical basis. Analyzing phenotypes of large numbers of yeast, nematode, and mouse mutants, we here describe the genomic patterns of pleiotropy. We show that the fraction of traits altered appreciably by the deletion of a gene is minute for most genes and the gene–trait relationship is highly modular. The standardized size of the phenotypic effect of a gene on a trait is approximately normally distributed with variable SDs for different genes, which gives rise to the surprising observation of a larger per-trait effect for genes affecting more traits. This scaling property counteracts the pleiotropy-associated reduction in adaptation rate (i.e., the “cost of complexity”) in a nonlinear fashion, resulting in the highest adaptation rate for organisms of intermediate complexity rather than low complexity. Intriguingly, the observed scaling exponent falls in a narrow range that maximizes the optimal complexity. Together, the genome-wide observations of overall low pleiotropy, high modularity, and larger per-trait effects from genes of higher pleiotropy necessitate major revisions of theoretical models of pleiotropy and suggest that pleiotropy has not only allowed but also promoted the evolution of complexity.     

Brief Report: Cooperation loci are more pleiotropic than private loci in the bacterium Pseudomonas aeruginosa

Pleiotropy may affect the maintenance of cooperation by limiting cheater mutants if such mutants lose other important traits. If pleiotropy limits cheaters, selection may favor cooperation loci that are more pleiotropic. However, the same should not be true for private loci with functions unrelated to cooperation. Pleiotropy in cooperative loci has mostly been studied with single loci and has not been measured on a wide scale or compared to a suitable set of control loci with private functions. I remedy this gap by comparing genomic measures of pleiotropy in previously identified cooperative and private loci in Pseudomonas aeruginosa. I found that cooperative loci in P. aeruginosa tended to be more pleiotropic than private loci according to the number of protein–protein interactions, the number of gene ontology terms, and gene expression specificity. These results show that pleiotropy may be a general way to limit cheating and that cooperation may shape pleiotropy in the genome.     

Dissecting the genetic architecture of lipids, lipoproteins, and apolipoproteins: lessons from twin studies

We review the ways in which twin studies have been used to investigate the genetic architecture of lipids, lipoproteins, and apolipoproteins. We focus on the age dependency of genetic effects and the importance of pleiotropy for the lipid system. Finally, consequences are discussed of age dependency and pleiotropy for the design and power of twin studies aimed at detecting the actual quantitative trait loci (QTLs) involved. It is concluded that twin studies have played an important role and will remain highly valuable for the elucidation of the genetic architecture of lipids, lipoproteins, and apolipoproteins. Twins can efficiently be used to identify the location and function of QTLs. Taking account of pleiotropy and age-dependent gene expression in study design and data analysis will improve the power and efficiency to find these QTLs for components of the lipid system.