Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors
Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors
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DOI：
10.1161/01.cir.97.12.1129
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发表时间：
1998-03-31
期刊：
影响因子：
37.8
通讯作者：
Liao, JK
中科院分区：
文献类型：
--
作者：
Laufs, U;La Fata, V;Liao, JK
氧化低密度脂蛋白（ox-LDL）部分通过降低内皮细胞一氧化氮（NO）的可用性而引起内皮功能障碍。尽管HMG CoA还原酶抑制剂通过降低血清胆固醇水平来恢复内皮功能，但尚不清楚它们是否也可以直接上调内皮NO合酶（ecNOS）活性。（50 μ g/mL硫代巴比妥酸反应性物质12 - 16 nmol/mg）在HMG CoA还原酶抑制剂辛伐他汀和洛伐他汀存在下，ox-LDL以时间依赖性方式降低ecNOS mRNA和蛋白水平（72小时后分别降低91 +/- 4%和67 +/- 8%）。辛伐他汀（1 μ mol/L）和洛伐他汀（10 μ mol/L）分别上调ecNOS表达3.8倍和3.6倍，并完全阻止ox-LDL下调ecNOS表达。辛伐他汀对ecNOS表达的影响与ecNOS活性的变化相关。虽然单独使用L-甲羟戊酸不影响ecNOS表达，但与L-甲羟戊酸共同处理可完全逆转辛伐他汀对ecNOS表达的上调。放线菌素D研究表明，辛伐他汀稳定ecNOS mRNA（tau（1/2），43与35小时）。用-1.6 kb的ecNOS启动子构建体进行的核运行试验和瞬时转染研究表明，辛伐他汀不影响ecNOS基因的转录。结论-内皮HMG CoA还原酶的抑制主要通过转录后机制上调ecNOS的表达。这些发现表明，HMG CoA还原酶抑制剂可能对动脉粥样硬化有有益的影响，超出了通过增加ecNOS活性降低血清胆固醇的作用。
Background - Oxidized low-density lipoprotein (ox-LDL) causes endothelial dysfunction in part by decreasing the availability of endothelial nitric oxide (NO). Although HMG CoA reductase inhibitors restore endothelial function by reducing serum cholesterol levels, it is not known whether they can also directly upregulate endothelial NO synthase (ecNOS) activity.Methods and Results - Human saphenous vein endothelial cells were treated with ox-LDL (50 mu g/mL thiobarbituric acid reactive substances 12 to 16 nmol/mg) in the presence of HMG CoA reductase inhibitors simvastatin and lovastatin, In a time-dependent manner, ox-LDL decreased ecNOS mRNA and protein levels (91 +/- 4% and 67 +/- 8% reduction after 72 hours, respectively), Both simvastatin (1 mu mol/L) and lovastatin (10 mu mol/L) upregulated ecNOS expression by 3.8-fold and 3.6-fold, respectively, and completely prevented its downregulation by ox-LDL. These effects of simvastatin on ecNOS expression correlated with changes in ecNOS activity, Although L-mevalonate alone did not affect ecNOS expression, cotreatment with L-mevalonate completely reversed ecNOS upregulation by simvastatin. Actinomycin D studies revealed that simvastatin stabilized ecNOS mRNA (tau(1/2), 43 versus 35 hours). Nuclear run-on assays and transient transfection studies with a -1.6 kb ecNOS promoter construct showed that simvastatin did not affect ecNOS gene transcription.Conclusions - Inhibition of endothelial HMG CoA reductase upregulates ecNOS expression predominantly by posttranscriptional mechanisms. These findings suggest that HMG CoA reductase inhibitors may have beneficial effects in atherosclerosis beyond that attributed to the lowering of serum cholesterol by increasing ecNOS activity.