Laufs Ulrich, Gertz Karen, Dirnagl Ulrich, Böhm Michael, Nickenig Georg, Endres Matthias
Medizinische Klinik und Poliklinik der Universität des Saarlandes, Innere Medizin III, 66421 Homburg, Germany.
Brain Res. 2002 Jun 28;942(1-2):23-30. doi: 10.1016/s0006-8993(02)02649-5.
HMG-CoA reductase inhibitors (statins) are cholesterol-lowering drugs and reduce the risk of myocardial infarction and stroke. In this study we investigated whether rosuvastatin, a new, potent HMG-CoA reductase inhibitor, upregulates endothelial nitric oxide (NO) expression and activity and protects from cerebral ischaemia in mice. Endothelial cells in culture and 129/SV mice were chronically treated with rosuvastatin. The expression and activity of endothelial NO synthase (eNOS) was determined by reverse-transcriptase polymerase chain reaction (RT-PCR), Western blotting and arginine-citrulline assays. Cerebral ischaemia was induced by occlusion of the middle cerebral artery (MCAo) for 2 h and infarct size was determined after 22 h of reperfusion. Treatment of endothelial cells with rosuvastatin concentration- and time-dependently upregulated eNOS mRNA and protein expression. In aortas of 129/SV wild-type mice, treatment with 0.2, 2, and 20 mg kg(-1) rosuvastatin subcutaneously (s.c.) for 10 days significantly upregulated eNOS mRNA by 50, 142, and 205%, respectively. NOS activity was significantly increased by 75, 145, and 320%, respectively. Stroke volume after 2-h MCAo was reduced by 27, 56, and 50% (for 0.2, 2 and 20 mg kg(-1), respectively). Serum cholesterol and triglygeride levels were not significantly lowered by the treatment. The novel HMG-CoA reductase inhibitor rosuvastatin dose-dependently upregulates eNOS expression and activity and protects from cerebral ischaemia in mice. The effects are independent of changes in cholesterol levels and are equivalent or even superior to the protective effects by simvastatin and atorvastatin in this animal model.
3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂（他汀类药物）是降胆固醇药物，可降低心肌梗死和中风的风险。在本研究中，我们调查了新型强效3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂瑞舒伐他汀是否上调内皮型一氧化氮（NO）的表达和活性，并保护小鼠免受脑缺血损伤。用瑞舒伐他汀对培养的内皮细胞和129/SV小鼠进行长期处理。通过逆转录聚合酶链反应（RT-PCR）、蛋白质印迹法和精氨酸-瓜氨酸测定法测定内皮型一氧化氮合酶（eNOS）的表达和活性。通过闭塞大脑中动脉（MCAo）2小时诱导脑缺血，并在再灌注22小时后测定梗死面积。用瑞舒伐他汀处理内皮细胞，eNOS mRNA和蛋白质表达呈浓度和时间依赖性上调。在129/SV野生型小鼠的主动脉中，皮下注射（s.c.）0.2、2和20 mg kg-1瑞舒伐他汀10天，eNOS mRNA分别显著上调50%、142%和205%。NOS活性分别显著增加75%、145%和320%。2小时MCAo后的中风体积分别减少27%、56%和50%（分别对应0.2、2和20 mg kg-1）。治疗后血清胆固醇和甘油三酯水平没有显著降低。新型3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂瑞舒伐他汀剂量依赖性地上调eNOS表达和活性，并保护小鼠免受脑缺血损伤。这些作用与胆固醇水平的变化无关，并且在该动物模型中与辛伐他汀和阿托伐他汀的保护作用相当甚至更优。
