Department of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom.
Thromb Haemost. 2012 Nov;108(5):840-8. doi: 10.1160/TH12-05-0337. Epub 2012 Aug 7.
Vascular oxidative stress is a key feature of atherogenesis, and targeting vascular redox signalling is a rational therapeutic goal in vascular disease pathogenesis. 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors or statins are potent lipid-lowering drugs that improve cardiovascular outcomes. It is now widely accepted that cardiovascular disease prevention by statins is dependent not only on their lipid lowering effects, but also on their beneficial effects on vascular redox signalling. Cell culture and animal models have provided important findings on the effects of statins on vascular redox and nitric oxide bioavailability. Recent evidence from studies on human vessels has further enhanced our understanding of the "pleiotropic" effects of statins on vascular wall. Reversal of endothelial dysfunction in human vessels by statins is dependent on the mevalonate pathway and Rac1 inhibition. These critical steps are responsible for reducing NADPH-oxidase activity and improving tetrahydrobiopterin bioavailability and nitric oxide synthase (NOS) coupling in human vessels. However, mevalonate pathway inhibition has been also held responsible for some of the side effects observed after statin treatment. In this review we summarise the existing knowledge on the effects of statins on vascular biology by discussing key findings from basic science as well as recent evidence from translational studies in humans. Finally, we discuss emerging aspects of statin pleiotropy, such as their effects on adipose tissue biology and adipokine synthesis that may light additional mechanistic links between statin treatment and improvement of clinical outcome in primary and secondary prevention.
血管氧化应激是动脉粥样硬化形成的一个关键特征，针对血管氧化还原信号转导是血管疾病发病机制中的一个合理治疗目标。3-羟基-3-甲基戊二酰辅酶 A 还原酶抑制剂或他汀类药物是强效的降脂药物，可改善心血管结局。现在人们普遍认为，他汀类药物预防心血管疾病不仅依赖于它们的降脂作用，还依赖于它们对血管氧化还原信号转导的有益作用。细胞培养和动物模型为他汀类药物对血管氧化还原和一氧化氮生物利用度的影响提供了重要的发现。最近来自人类血管研究的证据进一步增强了我们对他汀类药物对血管壁“多效性”作用的理解。他汀类药物逆转人类血管内皮功能障碍依赖于甲羟戊酸途径和 Rac1 抑制。这些关键步骤负责降低 NADPH 氧化酶活性，改善四氢生物蝶呤生物利用度和人类血管中一氧化氮合酶（NOS）偶联。然而，甲羟戊酸途径抑制也被认为是他汀类药物治疗后观察到的一些副作用的原因。在这篇综述中，我们通过讨论基础科学的关键发现以及人类转化研究的最新证据，总结了他汀类药物对血管生物学影响的现有知识。最后，我们讨论了他汀类药物多效性的新出现方面，例如它们对脂肪组织生物学和脂肪因子合成的影响，这可能为他汀类药物治疗与原发性和继发性预防中临床结局改善之间的机制联系提供更多线索。
