糖化apoA-I诱导血管内皮胰岛素抵抗效应及机制研究

Apolipoprotein A-I (apoA-I) is glycated in type2 diabetes mellitus and associated with diabetic vasculopathy. Our studies have shown that: glycated apoA-I ①induces systemic insulin resistance and vascular impairment in C57Bl/6 mice; ② promoted atherogenesis in apoE-KO mice; ③ induces arterial endothelial insulin resistance including suppression of insulin signal pathway (IRS-1/Akt/eNOS), and decrement of NO synthesis. Microarray analysis shows, with verification in cell experiments, that glycated apoA-I significantly up-regulates S100A14 and erbB2 expression, and p38MAPK pathway activity in endothelial cells. Since S100A14 is a ligand of receptor erbB2 and erbB2 is closely related to hepatic insulin resistance, we assume that S100A14-erbB2-P38MAPK pathway may be critically involved in vascular insulin resistance and subsequent atherogenesis. In the next step, we will investigate the pathogenic effect of glycated apoA-I in cell experiments using RNA interfere, specific inhibitors, and in animal models (wide-type and S100A14 knockout mice). The mechanism of glycated apoA-I regarding S100A14-erbB2-P38MAPK pathway in the development of vascular insulin resistance and atherogenesis will be tested.

糖尿病时载脂蛋白A-I发生糖化修饰，促进血管并发症。我们发现：糖化apoA-I①诱导小鼠全身胰岛素抵抗，血压升高，损伤血管功能；②促进apoE敲除小鼠动脉粥样硬化斑块发生；③促进动脉内皮细胞IRS-1丝氨酸残基磷酸化并抑制胰岛素信号通路IRS-1-Akt-eNOS活性，减少内源性NO生成。芯片发现并证实，糖化apoA-I显著上调内皮细胞中S100A14和erbB2表达，并激活P38MAPK。根据文献，S10014与erbB2结合，后者参与肝脏胰岛素抵抗，提示S100A14-erbB2-P38MAPK途径介导了糖化apoA-I引起的血管内皮胰岛素抵抗和血管病变。后续将运用siRNA技术、通路抑制剂和野生型、S100A14敲除小鼠等探讨糖化apoA-I引起血管内皮胰岛素抵抗并继而导致动脉粥样硬化的机制，揭示S100A14—erbB2—P38MAPK通路在糖化apoA-I致病中的作用。

糖尿病时载脂蛋白A-I发生糖化修饰，促进血管并发症。我们发现：糖化apoA-I①诱导小鼠全身胰岛素抵抗，血压升高，损伤血管功能；②促进apoE敲除小鼠动脉粥样硬化斑块发生；③促进动脉内皮细胞IRS-1丝氨酸残基磷酸化并抑制胰岛素信号通路IRS-1-Akt-eNOS活性，减少内源性NO生成。芯片发现并证实，糖化apoA-I显著上调内皮细胞中S100A14和erbB2表达，并激活P38MAPK。根据文献，S10014与erbB2结合，后者参与肝脏胰岛素抵抗，提示S100A14-erbB2-P38MAPK途径介导了糖化apoA-I引起的血管内皮胰岛素抵抗和血管病变。后续将运用siRNA技术、通路抑制剂和野生型、S100A14敲除小鼠等探讨糖化apoA-I引起血管内皮胰岛素抵抗并继而导致动脉粥样硬化的机制，揭示S100A14—erbB2—P38MAPK通路在糖化apoA-I致病中的作用。