Rikitake Yoshiyuki, Liao James K
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Circ Res. 2005 Dec 9;97(12):1232-5. doi: 10.1161/01.RES.0000196564.18314.23.
The lipid-lowering drugs, 3-hydroxy-3-methylgulutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins, are used in the prevention and treatment of cardiovascular diseases. Recent experimental and clinical studies suggest that statins may exert vascular protective effects beyond cholesterol reduction. For example, statins improve endothelial function by cholesterol-dependent and -independent mechanisms. The cholesterol-independent or "pleiotropic" effects of statins include the upregulation and activation of endothelial NO synthase (eNOS). Because statins inhibit an early step in the cholesterol biosynthetic pathway, they also inhibit the synthesis of isoprenoids such as farnesylpyrophosphate and geranylgeranylpyrophosphate, which are important posttranslational lipid attachments for intracellular signaling molecules such as the Rho GTPases. Indeed, decrease in Rho GTPase responses as a consequence of statin treatment increases the production and bioavailability of endothelium-derived NO. The mechanism involves, in part, Rho/Rho-kinase (ROCK)-mediated changes in the actin cytoskeleton, which leads to decreases in eNOS mRNA stability. The regulation of eNOS by Rho GTPases, therefore, may be an important mechanism underlying the cardiovascular protective effect of statins.
降脂药物，即3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂或他汀类药物，用于预防和治疗心血管疾病。最近的实验和临床研究表明，他汀类药物可能在降低胆固醇之外发挥血管保护作用。例如，他汀类药物通过胆固醇依赖和非依赖机制改善内皮功能。他汀类药物的非胆固醇依赖性或“多效性”作用包括内皮型一氧化氮合酶（eNOS）的上调和激活。由于他汀类药物抑制胆固醇生物合成途径的早期步骤，它们还抑制类异戊二烯如法尼基焦磷酸和香叶基香叶基焦磷酸的合成，这些是细胞内信号分子如Rho GTP酶重要的翻译后脂质附着基团。实际上，他汀类药物治疗导致的Rho GTP酶反应降低会增加内皮源性一氧化氮的产生和生物利用度。该机制部分涉及Rho/Rho激酶（ROCK）介导的肌动蛋白细胞骨架变化，这会导致eNOS mRNA稳定性降低。因此，Rho GTP酶对eNOS的调节可能是他汀类药物心血管保护作用的重要潜在机制。
