A new HMG-CoA reductase inhibitor, rosuvastatin, exerts anti-inflammatory effects on the microvascular endothelium: the role of mevalonic acid
A new HMG-CoA reductase inhibitor, rosuvastatin, exerts anti-inflammatory effects on the microvascular endothelium: the role of mevalonic acid
复制标题
DOI：
10.1038/sj.bjp.0704070
复制
发表时间：
2001-06-01
影响因子：
7.3
通讯作者：
Scalia, R
中科院分区：
文献类型：
--
作者：
Stalker, TJ;Lefer, AM;Scalia, R
1最近的研究报道，羟甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂具有独立于其降脂特性的血管保护作用，包括抗炎作用。我们使用大鼠肠系膜微血管的活体显微镜检查瑞舒伐他汀（一种新的HMG-CoA还原酶抑制剂）对凝血酶诱导的白细胞-内皮细胞相互作用的影响。2研究前18小时腹膜内给予0.5和1.25 mg/kg（1）瑞舒伐他汀，在灌流0.5 μ mL-L凝血酶的大鼠肠系膜微血管中的移行。在研究前18小时，通过腹腔注射25 mg/kg甲羟戊酸逆转了瑞舒伐他汀的这种保护作用。3内皮细胞粘附分子P-选择素的免疫组织化学检测显示，在给予1.25 mg/kg瑞舒伐他汀的凝血酶刺激大鼠中，内皮细胞表面P-选择素表达降低了70%。此外，在大鼠主动脉节段中直接测定，瑞舒伐他汀可增强血管内皮释放一氧化氮（NO）。此外，瑞舒伐他汀未能减弱eNOS（-）小鼠肠周微静脉中的白细胞-内皮细胞相互作用。4这些数据表明，瑞舒伐他汀通过抑制内皮细胞粘附分子表达发挥重要的抗炎作用，并且瑞舒伐他汀的这种保护作用需要血管内皮释放一氧化氮。这些数据还表明，HMG-CoA还原酶抑制剂在体内的非降脂作用机制可能是由于内皮细胞内甲羟戊酸的形成或利用率降低所致。British Journal of Pharmacology（2001）。
1 Recent studies have reported that hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have vasculoprotective effects independent of their lipid-lowering properties, including anti-inflammatory actions. We used intravital microscopy of the rat mesenteric microvasculature to examine the effects of rosuvastatin, a new HMG-CoA reductase inhibitor, on leukocyte-endothelium interactions induced by thrombin.2 Intraperitoneal administration of 0.5 and 1.25 mg kg (1) rosuvastatin 18 h prior to the study, significantly and dose-dependently attenuated leukocyte rolling, adherence, and transmigration in the rat mesenteric microvasculature superfused with 0.5 u ml-l thrombin. This protective effect of rosuvastatin was reversed by intraperitoneal injection of 25 mg kg(-1) mevalonic acid 18 h before the study.3 Immunohistochemical detection of the endothelial cell adhesion molecule P-selectin showed a 70% decrease in endothelial cell surface expression of P-selectin in thrombin-stimulated rats given 1.25 mg kg(-1) rosuvastatin. In addition, rosuvastatin enhanced release of nitric oxide (NO) from the vascular endothelium as measured directly in rat aortic segments. Moreover, rosuvastatin failed to attenuate leukocyte-endothelium interactions in peri-intestinal venules of eNOS(-) mice.4 These data indicate that rosuvastatin exerts important anti-inflammatory effects via inhibition of endothelial cell adhesion molecule expression, and that this protective action of rosuvastatin requires release of nitric oxide by the vascular endothelium. These data also demonstrate that the mechanism of the non-lipid lowering actions of HMG-CoA reductase inhibitors in vivo may be due to reduced formation or availability of mevalonic acid within endothelial cells.British Journal of Pharmacology (2001).