Rho-GTPase and Atherosclerosis: Pleiotropic Effects of Statins

3 A (HMG-CoA) reductase inhibitors or statins are a class of medications with potent effects on reducing serum cholesterol level, and currently have been widely used in the primary and secondary prevention of atherosclerotic cardiovascular diseases (ASCVD). Previously, a substantial number of clinical studies consistently demonstrated that through decreasing serum cholesterol level, especially low-density lipoprotein (LDL) cholesterol level, statins effectively reduce the incidence of cardiovascular events such as acute myocardial infarction and ischemic stroke in subjects with dyslipidemia. 1–3 Nevertheless, interestingly and importantly, results from other clinical studies in subjects with normal cholesterol level suggest that statins have additional cardioprotective effects, now universally known as pleiotropic effects, which include immunomodulation, antiinflammation and anti-oxidation, endothelium protection, and pro-angiogenesis. Results from experimental and clinical research indicate that the pleiotropic effects of statins treatment are predominantly derived from its potent effects on inhibiting Rho-GTPase isoprenylation through reducing geranylgeranylpyrophosphate (GGPP) generation during cholesterol biosynthesis. The Rho-GTPase family includes nearly 20 members in humans, and RhoA, Rac1, and Cdc42 are the most studied members. They exert complex and important effects on regulating endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) production, vascular smooth muscle cells (VSMC) migration and proliferation, reactive oxygen species (ROS) generation, inflammatory cells infiltration, and foamcells formation. Currently, based on the attractive and beneficial effects of statins therapy on maintaining vascular homeostasis as well as improving inflammatory reaction and oxidative stress, many studies have been conducted to investigate whether the pleiotropic effects of statins regimen could contribute to better outcomes in diseases such as heart failure, arrhythmias, cardiac hypertrophy, and diabetes mellitus. With regard to the accumulating evidence that demonstrates the cardioprotective effects of statins therapy in past decades and aiming to improve our understanding about the mechanisms associated with the pleiotropic effects of statins, especially its effect on modulating Rho-GTPase and its effectors, in this review we first summarize data from previous published articles and then present our views for the direction of future studies.