Gertz Karen, Laufs Ulrich, Lindauer Ute, Nickenig Georg, Böhm Michael, Dirnagl Ulrich, Endres Matthias
Klinik und Poliklinik für Neurologie, Charité, Humboldt-Universität Berlin, Berlin, Germany.
Stroke. 2003 Feb;34(2):551-7. doi: 10.1161/01.str.0000054055.28435.bf.
Statins (3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors) reduce stroke damage independent of lipid lowering by upregulation of endothelial nitric oxide synthase (eNOS). Acute withdrawal of statin treatment may suppress endothelial NO production and impair vascular function.
To test this hypothesis, we treated 129/SV mice with atorvastatin (10 mg/kg) for 14 days and then withdrew treatment.
Treatment with atorvastatin conferred stroke protection by 40% after filamentous occlusion of the middle cerebral artery followed by reperfusion. Withdrawal of statin treatment, however, resulted in the loss of stroke protection after 2 and 4 days. In mouse aortas and brain vasculature, statins upregulated eNOS message 2.3- and 1.7-fold, respectively, as measured by reverse transcription-polymerase chain reaction. Withdrawal of statins resulted in 5- and 2.7-fold downregulation of eNOS in aorta and brain, respectively, after 2 days. Statin treatment decreased RhoA GTPase membrane expression to 48%, while withdrawal of statins resulted in 4-fold increase of RhoA in the membrane. Moreover, platelet factor 4 and beta-thromboglobulin in plasma were significantly downregulated by statin treatment, but withdrawal of statins resulted in a 2.9- and 3.1-fold upregulation after 2 days, respectively. Thrombus formation induced by ligature of the inferior vena cava was significantly reduced by statin treatment. When statin treatment was withdrawn, however, protection was lost between 2 and 4 days.
Acute termination of statin treatment results in a rapid loss of protection in mouse models of cerebral ischemia and thrombus formation independent of lipid lowering. In patients with acute or impending stroke, withdrawal of statins may impair outcome.
他汀类药物（3-羟基-3-甲基戊二酰辅酶A [HMG-CoA]还原酶抑制剂）通过上调内皮型一氧化氮合酶（eNOS），独立于降脂作用减轻卒中损伤。急性停用他汀类药物治疗可能会抑制内皮一氧化氮生成并损害血管功能。
为验证这一假说，我们用阿托伐他汀（10毫克/千克）治疗129/SV小鼠14天，然后停药。
大脑中动脉丝线闭塞再灌注后，阿托伐他汀治疗使卒中保护率提高40%。然而，停药2天和4天后，卒中保护作用丧失。通过逆转录聚合酶链反应检测，在小鼠主动脉和脑血管中，他汀类药物分别使eNOS信使核糖核酸上调2.3倍和1.7倍。停药2天后，主动脉和大脑中eNOS分别下调5倍和2.7倍。他汀类药物治疗使RhoA GTP酶膜表达降至48%，而停药后膜内RhoA增加4倍。此外，他汀类药物治疗显著下调血浆中的血小板因子4和β-血小板球蛋白，但停药2天后分别上调2.9倍和3.1倍。他汀类药物治疗显著减少下腔静脉结扎诱导的血栓形成。然而，停药后，2至4天内保护作用丧失。
急性停用他汀类药物治疗会导致小鼠脑缺血和血栓形成模型中迅速丧失保护作用，且与降脂无关。对于急性或即将发生卒中的患者，停用他汀类药物可能会影响预后。
