Translating the effects of statins: From redox regulation to suppression of vascular wall inflammation
Translating the effects of statins: From redox regulation to suppression of vascular wall inflammation
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DOI：
10.1160/th12-05-0337
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发表时间：
2012-11-01
影响因子：
6.7
通讯作者：
Antoniades, Charalambos
中科院分区：
文献类型：
--
作者：
Antonopoulos, Alexios S.;Margaritis, Marios;Antoniades, Charalambos
血管氧化应激是动脉粥样硬化形成的关键特征，靶向血管氧化还原信号是血管疾病发病机制中合理的治疗目标。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有效的降脂药物，可改善心血管预后。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其降脂作用，还依赖于其对血管氧化还原信号的有益作用。细胞培养和动物模型提供了他汀类药物对血管氧化还原和一氧化氮生物利用度影响的重要发现。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的“多效性”作用的理解。他汀类药物逆转人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，提高四氢生物蝶呤的生物利用度和一氧化氮合酶（NOS）在人体血管中的偶联。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主要发现以及最近来自人类转化研究的证据，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，这可能会在他汀类药物治疗与一级和二级预防临床结果改善之间建立额外的机制联系。
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.