Oesterle Adam, Laufs Ulrich, Liao James K
From the Section of Cardiology, Department of Medicine, The University of Chicago, IL (A.O., J.K.L.); and Division of Cardiology, Department of Medicine, The University of Saarland, Homburg, Germany (U.L.).
Circ Res. 2017 Jan 6;120(1):229-243. doi: 10.1161/CIRCRESAHA.116.308537.
The statins have been used for 30 years to prevent coronary artery disease and stroke. Their primary mechanism of action is the lowering of serum cholesterol through inhibiting hepatic cholesterol biosynthesis thereby upregulating the hepatic low-density lipoprotein (LDL) receptors and increasing the clearance of LDL-cholesterol. Statins may exert cardiovascular protective effects that are independent of LDL-cholesterol lowering called pleiotropic effects. Because statins inhibit the production of isoprenoid intermediates in the cholesterol biosynthetic pathway, the post-translational prenylation of small GTP-binding proteins such as Rho and Rac, and their downstream effectors such as Rho kinase and nicotinamide adenine dinucleotide phosphate oxidases are also inhibited. In cell culture and animal studies, these effects alter the expression of endothelial nitric oxide synthase, the stability of atherosclerotic plaques, the production of proinflammatory cytokines and reactive oxygen species, the reactivity of platelets, and the development of cardiac hypertrophy and fibrosis. The relative contributions of statin pleiotropy to clinical outcomes, however, remain a matter of debate and are hard to quantify because the degree of isoprenoid inhibition by statins correlates to some extent with the amount of LDL-cholesterol reduction. This review examines some of the currently proposed molecular mechanisms for statin pleiotropy and discusses whether they could have any clinical relevance in cardiovascular disease.
他汀类药物已被用于预防冠状动脉疾病和中风30年。它们的主要作用机制是通过抑制肝脏胆固醇生物合成来降低血清胆固醇，从而上调肝脏低密度脂蛋白（LDL）受体并增加LDL胆固醇的清除率。他汀类药物可能发挥独立于降低LDL胆固醇的心血管保护作用，称为多效性作用。由于他汀类药物抑制胆固醇生物合成途径中类异戊二烯中间体的产生，小GTP结合蛋白（如Rho和Rac）的翻译后异戊二烯化及其下游效应器（如Rho激酶和烟酰胺腺嘌呤二核苷酸磷酸氧化酶）也受到抑制。在细胞培养和动物研究中，这些作用会改变内皮型一氧化氮合酶的表达、动脉粥样硬化斑块的稳定性、促炎细胞因子和活性氧的产生、血小板的反应性以及心脏肥大和纤维化的发展。然而，他汀类药物多效性对临床结局的相对贡献仍存在争议，且难以量化，因为他汀类药物对类异戊二烯的抑制程度在一定程度上与LDL胆固醇降低的量相关。本综述探讨了目前提出的一些他汀类药物多效性的分子机制，并讨论了它们在心血管疾病中是否具有任何临床相关性。
