Wagner A H, Köhler T, Rückschloss U, Just I, Hecker M
Department of Cardiovascular Physiology, University of Göttingen, Germany.
Arterioscler Thromb Vasc Biol. 2000 Jan;20(1):61-9. doi: 10.1161/01.atv.20.1.61.
Three 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (HCRIs), atorvastatin, pravastatin, and cerivastatin, inhibited phorbol ester-stimulated superoxide anion (O(2)(-)) formation in endothelium-intact segments of the rat aorta in a time- and concentration-dependent manner (maximum inhibition of 70% after 18 hours at 1 to 10 micromol/L). The HMG-CoA reductase product mevalonic acid (400 micromol/L) reversed the inhibitory effect of the HCRIs, which, conversely, was mimicked by inactivation of p21 Rac with Clostridium sordellii lethal toxin but not by inactivation of p21 Rho with Clostridium botulinum exoenzyme (C3). A mevalonate-sensitive inhibition of phorbol ester-stimulated O(2)(-) formation by atorvastatin was also observed in porcine cultured endothelial cells and in a murine macrophage cell line. In the rat aorta, no effect of the HCRIs on protein kinase C, NADPH oxidase, or superoxide dismutase (SOD) activity and expression was detected, whereas that of endothelial nitric oxide (NO) synthase was enhanced approximately 2-fold. Moreover, exposure of the segments to atorvastatin resulted in a significant improvement of endothelium-dependent NO-mediated relaxation, and this effect was abolished in the presence of SOD. Taken together, these findings suggest that in addition to augmenting endothelial NO synthesis, HCRIs inhibit endothelial O(2)(-) formation by preventing the isoprenylation of p21 Rac, which is critical for the assembly of NADPH oxidase after activation of protein kinase C. The resulting shift in the balance between NO and O(2)(-) in the endothelium improves endothelial function even in healthy blood vessels and therefore may provide a reasonable explanation for the beneficial effects of HCRIs in patients with coronary heart disease in addition to or as an alternative to the reduction in serum LDL cholesterol.
三种3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂（HCRIs），阿托伐他汀、普伐他汀和西立伐他汀，以时间和浓度依赖性方式抑制大鼠主动脉内皮完整节段中佛波酯刺激的超氧阴离子（O₂⁻）形成（在1至10微摩尔/升浓度下18小时后最大抑制率达70%）。HMG-CoA还原酶产物甲羟戊酸（400微摩尔/升）可逆转HCRIs的抑制作用，相反，用索氏梭菌致死毒素使p21 Rac失活可模拟该抑制作用，但肉毒杆菌外毒素（C3）使p21 Rho失活则不能。在猪培养的内皮细胞和小鼠巨噬细胞系中也观察到阿托伐他汀对佛波酯刺激的O₂⁻形成有甲羟戊酸敏感的抑制作用。在大鼠主动脉中，未检测到HCRIs对蛋白激酶C、NADPH氧化酶或超氧化物歧化酶（SOD）活性及表达有影响，而内皮型一氧化氮（NO）合酶的活性增强了约2倍。此外，将节段暴露于阿托伐他汀可使内皮依赖性NO介导的舒张功能显著改善，且在超氧化物歧化酶存在时该作用被消除。综上所述，这些发现表明，除了增强内皮NO合成外，HCRIs通过阻止p21 Rac的异戊二烯化来抑制内皮O₂⁻形成，这对于蛋白激酶C激活后NADPH氧化酶的组装至关重要。内皮中NO和O₂⁻平衡的这种变化即使在健康血管中也能改善内皮功能，因此这可能为HCRIs在冠心病患者中除降低血清低密度脂蛋白胆固醇之外或作为其替代作用的有益效果提供合理的解释。
