Selwyn Andrew P
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital & Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
Curr Atheroscler Rep. 2007 Oct;9(4):281-5. doi: 10.1007/s11883-007-0034-3.
Cardiovascular risk factors, particularly low-density lipoproteins (LDL), give rise to atherosclerosis and its complications by triggering a dysfunctional endothelium, inflammation, and a procoagulant vascular surface. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibition by statins leads to a fall in circulating and plaque LDL concentrations and improvement in many cellular dysfunctions, but controlled trials only show partial benefit with regard to myocardial infarction, stroke, and cardiovascular death. Emerging clinical evidence now shows that these risk factors also stimulate the activation (isoprenylation) of small G-binding proteins and, through their effectors (Rho-associated kinase) they can activate many or most of the subcellular and vessel wall pathophysiology of atherosclerosis. Inhibition of Rho-kinase can improve these dysfunctions with no changes in LDL. Similarly, statins can diminish the activation of these small G-binding proteins and their downstream effectors in atherosclerosis. This review compares and contrasts the effects of statins on atherosclerosis that are related to changes in LDL with those effects occurring through these alternate lipid pathways, and suggests that the therapeutic control of these small G-binding proteins and their downstream effectors may significantly add to the partial benefits of using statins in patients with atherosclerotic heart disease.
心血管危险因素，尤其是低密度脂蛋白（LDL），通过引发内皮功能障碍、炎症和促凝血血管表面，导致动脉粥样硬化及其并发症。他汀类药物对3-羟基-3-甲基戊二酰辅酶A（HMG CoA）还原酶的抑制作用会导致循环和斑块中LDL浓度下降，并改善许多细胞功能障碍，但对照试验仅显示在心肌梗死、中风和心血管死亡方面有部分益处。新出现的临床证据表明，这些危险因素还会刺激小G结合蛋白的激活（异戊二烯化），并通过其效应器（Rho相关激酶）激活动脉粥样硬化的许多或大部分亚细胞和血管壁病理生理过程。抑制Rho激酶可以改善这些功能障碍，而LDL无变化。同样，他汀类药物可以减少动脉粥样硬化中这些小G结合蛋白及其下游效应器的激活。本综述比较并对比了他汀类药物对动脉粥样硬化的影响，这些影响与LDL的变化有关，以及通过这些替代脂质途径产生的影响，并表明对这些小G结合蛋白及其下游效应器的治疗性控制可能会显著增加他汀类药物在动脉粥样硬化性心脏病患者中带来的部分益处。
