Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo A specific vascular action of insulin
Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo A specific vascular action of insulin
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DOI：
10.1161/01.cir.101.6.676
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发表时间：
2000-02-15
期刊：
影响因子：
37.8
通讯作者：
King, GL
中科院分区：
文献类型：
--
作者：
Kuboki, K;Jiang, ZY;King, GL
背景-胰岛素的血管舒张作用可以是急性的，也可以在1 - 7小时内随时间增加，这表明胰岛素可以增强内皮细胞中内皮型一氧化氮合酶（eNOS）的表达。本研究的目的是描述胰岛素调节内皮细胞和血管组织中eNOS表达的程度和信号通路。方法和结果生理浓度的胰岛素（10（-10）至10（-7）mmol/L）在培养的牛主动脉内皮细胞中孵育7至8小时后，eNOS mRNA、蛋白和活性水平增加2倍。胰岛素增强了Zucker瘦大鼠微血管中eNOS基因的表达，但不增强胰岛素抵抗Zucker肥胖大鼠微血管中eNOS基因的表达磷脂酰肌醇-3激酶（PI-3 kinase）抑制剂降低胰岛素对eNOS基因表达的影响，但一般蛋白激酶C（PKC）抑制剂GF 109203 X或PKC β亚型抑制剂LY 333531增强eNOS表达。相反，PKC激活剂抑制胰岛素对PI-3激酶和eNOS mRNA水平的激活。PKC β亚型在内皮细胞中的过表达抑制了胰岛素对内皮细胞和微血管中eNOS表达和PI-3激酶活性的刺激。结论胰岛素可通过PI-3激酶的激活调节内皮细胞和微血管中eNOS基因的表达。因此，胰岛素可以长期调节血管张力。如在胰岛素抵抗和糖尿病中，血管组织中PKC的活化可抑制PI-3激酶活性和eNOS表达，并可导致这些病理状态下的内皮功能障碍。
Background-The vasodilatory effect of insulin can be acute or increase with time from 1 to 7 hours, suggesting that insulin may enhance the expression of endothelial nitric oxide synthase (eNOS) in endothelial cells. The objective of the present study was to characterize the extent and signaling pathways by which insulin regulates the expression of eNOS in endothelial cells and vascular tissues.Methods and Results-Physiological concentrations of insulin (10(-10) to 10(-7) mmol/L) increased the levels of eNOS mRNA, protein, and activity by 2-fold after 7 to 8 hours of incubation in cultured bovine aortic endothelial cells. Insulin enhanced eNOS gene expression in microvessels isolated from Zucker lean rats but not from insulin-resistant Zucker fatty rats. Inhibitors of phosphatidylinositol-3 kinase (PI-3 kinase) decreased the effect of insulin on eNOS gene expression, but a general protein kinase C (PKC) inhibitor, GF109203X or PKC beta isoform inhibitor, LY333531 enhanced eNOS expression. In contrast, PKC activators inhibited both the activation by insulin of PI-3 kinase and eNOS mRNA levels. Overexpression of PKC beta isoform in endothelial cells inhibited the stimulation by insulin of eNOS expression and PI-3 kinase activities in parallel.Conclusions-Insulin can regulate the expression of eNOS gene, mediated by the activation of PI-3 kinase, in endothelial cells and microvessels. Thus, insulin may chronically modulate vascular tone. The activation of PKC in the vascular tissues as in insulin resistance and diabetes may inhibit PI-3 kinase activity and eNOS expression and may lead to endothelial dysfunctions in these pathological states.