Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells
Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells
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DOI：
10.1172/jci1500
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发表时间：
1998-06-15
影响因子：
15.9
通讯作者：
Lamas, S
中科院分区：
文献类型：
--
作者：
Hernández-Perera, O;Pérez-Sala, D;Lamas, S
与动脉粥样硬化相关的内皮功能障碍归因于L-精氨酸-一氧化氮（NO）-cGMP通路的改变或内皮素-I（ET-1）过量。3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂（他汀类药物）已被证明可以改善内皮功能。然而，这种观察的生理基础在很大程度上是未知的。我们研究了阿托伐他汀和辛伐他汀对牛主动脉内皮细胞ET-1前体mRNA表达和ET-1合成以及内皮型一氧化氮合酶（eNOS）转录和蛋白水平的影响。这些药物以浓度和时间依赖性方式抑制前proET-1 mRNA表达（最大抑制率为60-70%），并降低免疫反应性ET-1水平（25-50%）。这种抑制作用在氧化LDL（1-50 μ g/ml）存在下得以维持。未观察到前proET-1 mRNA半衰期的显著改变。此外，甲羟戊酸，而不是胆固醇，逆转他汀类药物介导的前proET-1 mRNA水平的下降。eNOS mRNA的表达减少氧化LDL的剂量依赖性的方式（高达57%的抑制），而天然LDL没有影响。他汀类药物可从mRNA和蛋白水平阻断氧化LDL对eNOS的抑制作用。因此，这些药物可能通过调节内皮血管活性因子的表达来影响血管张力。
Endothelial dysfunction associated with atherosclerosis has been attributed to alterations in the L-arginine-nitric oxide (NO)-cGMP pathway or to an excess of endothelin-l (ET-I). The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to ameliorate endothelial function. However, the physiological basis of this observation is largely unknown. We investigated the effects of Atorvastatin and Simvastatin on the pre-proET-1 mRNA expression and ET-1 synthesis and on the endothelial NO synthase (eNOS) transcript and protein levels in bovine aortic endothelial cells. These agents inhibited pre-proET-1 mRNA expression in a concentration- and time-dependent fashion (60-70% maximum inhibition) and reduced immunoreactive ET-1 levels (25-50%). This inhibitory effect was maintained in the presence of oxidized LDL (1-50 mu g/ml). No significant modification of pre-proET-1 mRNA half-life was observed. In addition, mevalonate, but not cholesterol, reversed the statin-mediated decrease of pre-proET-1 mRNA levels. eNOS mRNA expression was reduced by oxidized LDL in a dose-dependent fashion (up to 57% inhibition), whereas native LDL had no effect. Statins were able so prevent the inhibitory action exerted by oxidized LDL on eNOS mRNA and protein levels. Hence, these drugs might influence vascular tone by modulating the expression of endothelial vasoactive factors.