Yamakuchi Munekazu, Greer James J M, Cameron Scott J, Matsushita Kenji, Morrell Craig N, Talbot-Fox Karen, Baldwin William M, Lefer David J, Lowenstein Charles J
Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Circ Res. 2005 Jun 10;96(11):1185-92. doi: 10.1161/01.RES.0000170229.49776.81. Epub 2005 May 19.
Three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors protect the vasculature from inflammation and atherosclerosis by cholesterol dependent and cholesterol independent mechanisms. We hypothesized that HMG-CoA reductase inhibitors decrease exocytosis of Weibel-Palade bodies, endothelial cell granules whose contents promote thrombosis and vascular inflammation. We pretreated human aortic endothelial cells with simvastatin for 24 hours, then stimulated the cells with thrombin, and measured the amount of vWF released into the media. We then measured the effect of simvastatin on myocardial infarction in mice. Simvastatin decreased thrombin-stimulated Weibel-Palade body exocytosis by 89%. Simvastatin inhibited exocytosis in part by increasing synthesis of nitric oxide (NO), which S-nitrosylated N-ethylmaleimide sensitive factor (NSF), a critical regulator of exocytosis. Simvastatin treatment attenuated myocardial infarct size by 58% in wild-type but not eNOS knockout mice. Furthermore, simvastatin decreased endothelial exocytosis and neutrophil infiltration into ischemic-reperfused myocardium, which was mediated in part by P-selectin contained in Weibel-Palade bodies. However, simvastatin did not affect exocytosis and inflammation in myocardial infarcts of eNOS knockout mice. Inhibition of endothelial exocytosis is a novel mechanism by which HMG-CoA reductase inhibitors may reduce vascular inflammation, inhibit thrombosis, and protect the ischemic myocardium. These findings may explain part of the pleiotropic effects of statin therapy for patients with cardiovascular disease.
3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂通过胆固醇依赖性和胆固醇非依赖性机制保护血管免受炎症和动脉粥样硬化影响。我们推测HMG-CoA还原酶抑制剂可减少魏尔-帕拉德小体的胞吐作用，魏尔-帕拉德小体是内皮细胞颗粒，其内容物可促进血栓形成和血管炎症。我们用辛伐他汀预处理人主动脉内皮细胞24小时，然后用凝血酶刺激细胞，并测量释放到培养基中的血管性血友病因子（vWF）量。然后我们测量了辛伐他汀对小鼠心肌梗死的影响。辛伐他汀使凝血酶刺激的魏尔-帕拉德小体胞吐作用降低了89%。辛伐他汀部分通过增加一氧化氮（NO）的合成来抑制胞吐作用，NO使N-乙基马来酰亚胺敏感因子（NSF）发生S-亚硝基化，NSF是胞吐作用的关键调节因子。在野生型小鼠中，辛伐他汀治疗使心肌梗死面积缩小了58%，但在eNOS基因敲除小鼠中则没有。此外，辛伐他汀减少了内皮细胞胞吐作用以及中性粒细胞向缺血再灌注心肌的浸润，这部分是由魏尔-帕拉德小体中所含的P-选择素介导的。然而，辛伐他汀对eNOS基因敲除小鼠心肌梗死中的胞吐作用和炎症没有影响。抑制内皮细胞胞吐作用是HMG-CoA还原酶抑制剂减少血管炎症、抑制血栓形成和保护缺血心肌的一种新机制。这些发现可能解释了他汀类药物治疗心血管疾病患者多效性作用的部分原因。
