Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthase in mice
Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthase in mice
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DOI：
10.1161/01.str.32.4.980
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发表时间：
2001-04-01
期刊：
影响因子：
8.3
通讯作者：
Moskowitz, MA
中科院分区：
文献类型：
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作者：
Amin-Hanjani, S;Stagliano, NE;Moskowitz, MA
背景和目的：3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂（他汀类药物）可降低血清胆固醇，降低中风和心血管疾病的发病率。越来越多的证据表明，他汀类药物发挥其一些有益的影响，独立于降低胆固醇。事实上，我们以前已经证明，慢性辛伐他汀给药上调内皮型一氧化氮合酶（eNOS），导致更多的功能蛋白，脑血流量的增加，并在小鼠脑缺血模型的神经保护。在这份报告中，我们研究了他汀类药物家族的另一个成员是否共享这些效果，是否eNOS上调持续较长的treatment. Methods美伐他汀（2毫克/公斤或20毫克/公斤每天）被管理到18- 22克雄性小鼠7，14，或28天前2小时大脑中动脉闭塞与使用的细丝模型（n = 9至12）。在24小时评估神经功能缺损和脑梗死体积。在一个动物亚组（n=5）中监测动脉血压和气体、相对脑血流量和血液胆固醇水平。绝对脑血流量测定的[C-14]iodoamphetamine指示剂分馏技术（n=6），eNOS mRNA和蛋白质水平determined.Results-Mevastatin增加eNOS mRNA和蛋白质水平，减少梗死面积，并改善神经功能缺损的剂量和时间依赖性的方式。13天和25天高剂量治疗的保护作用最大（分别减少26%和37%的梗死）。胆固醇水平仅在治疗28天后降低，与梗死减少无关。基线绝对脑血流量高30%后，14天的高剂量treatment. Conclusions慢性预防性治疗与美伐他汀上调eNOS和增强脑血流量。这些变化发生在血清胆固醇水平没有变化的情况下，持续长达1个月的治疗，并导致大脑中动脉闭塞后的神经保护。
Background and Purpose-The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) lower serum cholesterol and decrease the incidence of stroke and cardiovascular disease. There is growing evidence that statins exert some of their beneficial effects independent of cholesterol lowering. Indeed, we have previously demonstrated that chronic simvastatin administration upregulates endothelial nitric oxide synthase (eNOS), resulting in more functional protein, augmentation of cerebral blood flow, and neuroprotection in a murine model of cerebral ischemia. In this report we examined whether another member of the statin family shared these effects and whether eNOS upregulation is sustained with longer treatment.Methods-Mevastatin (2 mg/kg or 20 mg/kg per day) was administered to 18- to 22-g male mice for 7, 14, or 28 days before 2-hour middle cerebral artery occlusion with the use of the filament model (n = 9 to 12). Neurological deficits and cerebral infarct volumes were assessed at 24 hours. Arterial blood pressure and gases, relative cerebral blood flow, and blood cholesterol levels were monitored in a subset of animals (n=5). Absolute cerebral blood flow was measured by the [C-14]iodoamphetamine indicator fractionation technique (n=6), eNOS mRNA and protein levels were determined.Results-Mevastatin increased levels of eNOS mRNA and protein, reduced infarct size, and improved neurological deficits in a dose- and time-dependent manner. Greatest protection was seen with 13- and 25-day high-dose treatment (26% and 37% infarct reduction, respectively). Cholesterol levels were reduced only after 28 days of treatment and did not correlate with infarct reduction. Baseline absolute cerebral blood flow was 30% higher after 14-day high-dose treatment.Conclusions-Chronic prophylactic treatment with mevastatin upregulated eNOS and augmented cerebral blood flow. These changes occurred in the absence of changes in serum cholesterol levels, were sustained for up to 1 month of treatment, and resulted in neuroprotection after middle cerebral artery occlusion.