Activation of vascular protein kinase C-β inhibits Akt-dependent endothelial nitric oxide synthase function in obesity-associated insulin resistance
Activation of vascular protein kinase C-β inhibits Akt-dependent endothelial nitric oxide synthase function in obesity-associated insulin resistance
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DOI：
10.2337/diabetes.55.03.06.db05-0771
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发表时间：
2006-03-01
期刊：
影响因子：
7.7
通讯作者：
King, GL
中科院分区：
文献类型：
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作者：
Naruse, K;Rask-Madsen, C;King, GL
血管组织中蛋白激酶C（PKC）的激活与内皮功能障碍和胰岛素抵抗有关。然而，血管PKC激活对胰岛素刺激的内皮型一氧化氮（NO）合酶（eNOS）调节的影响在肥胖相关的胰岛素抵抗中尚未得到表征。与Zucker瘦大鼠相比，Zucker肥胖大鼠主动脉中的二酰基甘油（DAG）浓度和PKC活性增加。胰岛素刺激的Akt磷酸化和cGMP浓度的增加（一种NO生物利用度的测量）在正常血糖-高胰岛素钳夹后在肥胖大鼠的主动脉中与瘦大鼠相比是钝化的，但在用PKC β抑制剂ruboxirin（LY 333531）治疗2周后部分恢复正常。在内皮细胞培养中，PKC β 1和-β 2的过度表达，而不是PKC α，-δ或-zeta，降低胰岛素刺激的Akt磷酸化和eNOS表达。PKC β 1和-β 2的过表达，而不是PKC α或-δ，也降低了血管内皮生长因子（VEGF）刺激的Akt磷酸化。在从只在血管细胞中过度表达PKC β 2的转基因小鼠中分离的微血管中，与野生型小鼠相比，胰岛素刺激的Akt磷酸化降低。因此，内皮细胞和血管组织中PKC β的激活抑制胰岛素和VEGF对Akt的激活，抑制胰岛素对Nkt依赖性eNOS的调节，并导致肥胖相关胰岛素抵抗中的内皮功能障碍。
Activation of protein kinase C (PKC) in vascular tissue is associated with endothelial dysfunction and insulin resistance. However, the effect of vascular PKC activation on insulin-stimulated endothelial nitric oxide (NO) synthase (eNOS) regulation has not been characterized in obesity-associated insulin resistance. Diacylglycerol (DAG) concentration and PKC activity were increased in the aorta of Zucker fatty compared with Zucker lean rats. Insulin-stimulated increases in Akt phosphorylation and cGMP concentration (a measure of NO bioavailability) after euglycemic-hyperinsulinemic clamp were blunted in the aorta of fatty compared with lean rats but were partly normalized after 2 weeks of treatment with the PKC beta inhibitor ruboxistaurin (LY333531). In endothelial cell culture, overexpression of PKC beta 1 and -beta 2, but not PKC alpha, -delta, or -zeta, decreased insulin-stimulated Akt phosphorylation and eNOS expression. Overexpression of PKC beta 1 and -beta 2, but not PKC alpha or -delta, also decreased Akt phosphorylation stimulated by vascular endothelial growth factor (VEGF). In microvessels isolated from transgenic mice overexpressing PKC beta 2 only in vascular cells, Akt phosphorylation stimulated by insulin was decreased compared with wild-type mice. Thus, activation of PKC beta in endothelial cells and vascular tissue inhibits Akt activation by insulin and VEGF, inhibits Nkt-dependent eNOS regulation by insulin, and causes endothelial dysfunction in obesity-associated insulin resistance.