Department of Pharmacology, Faculty of Pharmacy, Integral University, Lucknow, India.
Department of Bioengineering, Faculty of Engineering, Integral University, Lucknow, India.
Drug Res (Stuttg). 2022 Nov;72(9):477-486. doi: 10.1055/a-1873-1978. Epub 2022 Jul 22.
In 1976, Japanese microbiologist Akira Endo discovered the first statin as a product of the fungus that inhibited the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Their primary mode of action is to lower the blood cholesterol by decreasing hepatic cholesterol production, which upregulates hepatic low-density lipoprotein (LDL) receptors and increases LDL-cholesterol clearance. In addition to cholesterol lowering, statins inhibit other downstream products of the mevalonate pathway, causing the so-called pleiotropic effects. As a result of their pleiotropic effects statins modulate virtually all known processes of atherosclerosis and have beneficial effects outside the cardiovascular system Statins inhibit the post-translational prenylation of small GTP-binding proteins such as Rho, Rac, as well as their downstream effectors such as Rho kinase and nicotinamide adenine dinucleotide phosphate oxidases since they suppress the synthesis of isoprenoid intermediates in the cholesterol biosynthetic pathway altering the expression of endothelial nitric oxide synthase, the stability of atherosclerotic plaques, production of proinflammatory cytokines, reactive oxygen species, platelet reactivity, development of cardiac hypertrophy and fibrosis in cell culture and animal experiments. Inhibition of Rho and Rho-associated coiled-coil containing protein kinase (ROCK), has emerged as the principle mechanisms underlying the pleiotropic effects of statins. However, the relative contributions of statin pleiotropy to clinical outcomes are debatable and difficult to measure because the amount of isoprenoid inhibition by statins corresponds to some extent with the amount of LDL-cholesterol decrease. This article examines some of the existing molecular explanations underlying statin pleiotropy and discusses if they have clinical relevance in cardiovascular diseases.
1976 年，日本微生物学家 Endo 教授从一种真菌中发现了第一种他汀类药物，该真菌可抑制 3-羟基-3-甲基戊二酰辅酶 A 还原酶的活性。他汀类药物的主要作用机制是通过减少肝脏胆固醇的产生来降低血液中的胆固醇，从而上调肝脏的低密度脂蛋白（LDL）受体并增加 LDL 胆固醇的清除率。除了降低胆固醇外，他汀类药物还抑制了甲羟戊酸途径的其他下游产物，从而产生了所谓的多效性作用。由于其多效性作用，他汀类药物调节了动脉粥样硬化的几乎所有已知过程，并在心血管系统之外具有有益的作用。他汀类药物抑制 Rho、Rac 等小 GTP 结合蛋白的翻译后 prenylation，以及 Rho 激酶和烟酰胺腺嘌呤二核苷酸磷酸氧化酶等下游效应物，因为它们抑制了胆固醇生物合成途径中异戊烯基中间体的合成，从而改变了内皮一氧化氮合酶的表达、动脉粥样硬化斑块的稳定性、促炎细胞因子的产生、活性氧、血小板反应性、心脏肥厚和纤维化的发展在细胞培养和动物实验中。抑制 Rho 和 Rho 相关卷曲螺旋蛋白激酶（ROCK）已成为他汀类药物多效性作用的主要机制。然而，他汀类药物多效性对临床结局的相对贡献是有争议的，并且难以衡量，因为他汀类药物对异戊烯基的抑制程度在某种程度上与 LDL 胆固醇降低的程度相对应。本文考察了他汀类药物多效性的一些现有分子解释，并讨论了它们在心血管疾病中的临床相关性。
