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首页> 外文期刊>Circulation: An Official Journal of the American Heart Association >Apolipoprotein CIII links hyperlipidemia with vascular endothelial cell dysfunction.
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Apolipoprotein CIII links hyperlipidemia with vascular endothelial cell dysfunction.

机译：载脂蛋白CIII将高脂血症与血管内皮细胞功能障碍联系在一起。

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BACKGROUND: Apolipoprotein CIII (apoCIII) is a component of some triglyceride-rich very-low-density and low-density lipoprotein and is elevated in dyslipidemia with insulin resistance and the metabolic syndrome. We previously reported that apoCIII directly activates proinflammatory and atherogenic signaling in vascular endothelial cells through protein kinase C-beta (PKCbeta). Because PKCbeta impairs the response of vascular endothelial cells to insulin, we tested the hypothesis that apoCIII affects insulin signaling in vascular endothelial cells and its function in vitro and in vivo. METHODS AND RESULTS: ApoCIII inhibited insulin-induced tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), decreasing phosphatidylinositol 3-kinase (PI3K)/Akt activation in human umbilical vein endothelial cells. These effects of apoCIII led to reduced endothelial nitric oxide synthase (eNOS) activation and NO release into the media. ApoCIII activated PKCbeta in human umbilical vein endothelial cells, resulting in IRS-1 dysfunction via serine phosphorylation. ApoCIII also activated mitogen-activated protein kinase through PKCbeta. The impaired insulin signaling was restored by PKCbeta inhibitor or MEK1 inhibitor. ApoCIII-rich very-low-density lipoprotein and apoCIII impaired insulin signaling in the aorta of C57BL/6J mice and in human umbilical vein endothelial cells, which was recovered by PKCbeta inhibitor. They also inhibited endothelium-dependent relaxation of the aortas of C57BL/6J mice. In summary, apoCIII in very-low-density lipoprotein impaired insulin stimulation of NO production by vascular endothelium and induced endothelial dysfunction in vivo. This adverse effect of apoCIII was mediated by its activation of PKCbeta, which inhibits the IRS-1/PI3K/Akt/eNOS pathway. CONCLUSIONS: Our results suggest that apoCIII is a crucial link between dyslipidemia and insulin resistance in vascular endothelial cells with consequential deleterious effects on their atheroprotective functions.
机译：背景：载脂蛋白CIII（apoCIII）是一些富含甘油三酸酯的极低密度和低密度脂蛋白的组成部分，在血脂异常，胰岛素抵抗和代谢综合征中升高。我们以前曾报道过apoCIII通过蛋白激酶C-beta（PKCbeta）直接激活血管内皮细胞中的促炎和动脉粥样硬化信号。因为PKCbeta损害血管内皮细胞对胰岛素的反应，所以我们测试了apoCIII影响血管内皮细胞中胰岛素信号传导及其功能的假说。方法和结果：ApoCIII抑制了胰岛素诱导的胰岛素受体底物1（IRS-1）的酪氨酸磷酸化，降低了人脐静脉内皮细胞的磷脂酰肌醇3-激酶（PI3K）/ Akt活化。 apoCIII的这些作用导致内皮一氧化氮合酶（eNOS）活化减少，NO释放到培养基中。 ApoCIII激活人脐静脉内皮细胞中的PKCbeta，通过丝氨酸磷酸化导致IRS-1功能障碍。 ApoCIII还通过PKCbeta激活了促分裂原活化的蛋白激酶。受损的胰岛素信号可通过PKCbeta抑制剂或MEK1抑制剂恢复。富含ApoCIII的极低密度脂蛋白和apoCIII损害了C57BL / 6J小鼠主动脉和人脐静脉内皮细胞中的胰岛素信号传导，这些信号可通过PKCbeta抑制剂回收。它们还抑制了C57BL / 6J小鼠主动脉的内皮依赖性舒张。总之，极低密度脂蛋白中的apoCIII损害了胰岛素对血管内皮NO产生的刺激作用，并在体内诱导了内皮功能障碍。 apoCIII的这种不良反应是由其激活PKCbeta介导的，它抑制了IRS-1 / PI3K / Akt / eNOS途径。结论：我们的结果表明，载脂蛋白CIII是血脂异常和血管内皮细胞胰岛素抵抗之间的关键环节，因此对它们的动脉粥样硬化保护功能具有有害作用。

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