Impaired insulin-mediated vasorelaxation in diabetic Goto-Kakizaki rats is caused by impaired Akt phosphorylation.
Impaired insulin-mediated vasorelaxation in diabetic Goto-Kakizaki rats is caused by impaired Akt phosphorylation.
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DOI：
10.1152/ajpcell.00254.2008
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发表时间：
2009-02
期刊：
影响因子：
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通讯作者：
Jin Hee Lee;T. Palaia;L. Ragolia
中科院分区：
文献类型：
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作者：
Jin Hee Lee;T. Palaia;L. Ragolia
与2型糖尿病相关的胰岛素抵抗导致血管舒张受损。以前，我们发现肌球蛋白结合的磷酸酶底物MYPT 1的磷酸化，血管平滑肌细胞（VSMC）收缩的标志物，是负调节Akt（蛋白激酶B）磷酸化响应胰岛素刺激。在这项研究中，我们研究了Akt磷酸化在Goto-Kakizaki（GK）大鼠2型糖尿病模型中胰岛素诱导的血管舒张受损中的作用。GK VSMCs受损的基础和胰岛素诱导的Akt磷酸化，以及增加基础MYPT 1磷酸化，诱导型一氧化氮合酶（iNOS）的表达，和亚硝酸盐/硝酸盐的生产相比，Wistar-Kyoto控制。iNOS的表达和血管紧张素II（ANG）诱导的MYPT 1磷酸化的抑制在糖尿病GK VSMC中抵抗胰岛素的作用。我们还测量了完整的和裸露的GK主动脉的等长张力，并观察到显着受损的胰岛素诱导的血管舒张。腺病毒介导的GK VSMC中组成型活性Akt的过表达导致显著改善胰岛素敏感性，这是因为通过MYPT 1、肌球蛋白轻链去磷酸化和减少iNOS表达、S-亚硝基化和Survivin表达来抵消ANG II诱导的收缩信号传导。我们首次证明了GK糖尿病模型中存在Akt非依赖性iNOS表达，并且在糖尿病血管系统中观察到的胰岛素诱导的血管舒张缺陷可以通过活性Akt的过表达来恢复，这倡导了治疗糖尿病的新治疗策略。
Insulin resistance associated with Type 2 diabetes contributes to impaired vasorelaxation. Previously, we showed the phosphorylation of myosin-bound phosphatase substrate MYPT1, a marker of the vascular smooth muscle cell (VSMC) contraction, was negatively regulated by Akt (protein kinase B) phosphorylation in response to insulin stimulation. In this study we examined the role of Akt phosphorylation on impaired insulin-induced vasodilation in the Goto-Kakizaki (GK) rat model of Type 2 diabetes. GK VSMCs had impaired basal and insulin-induced Akt phosphorylation as well as increases in basal MYPT1 phosphorylation, inducible nitric oxide synthase (iNOS) expression, and nitrite/nitrate production compared with Wistar-Kyoto controls. Both iNOS expression and the inhibition of angiotensin (ANG) II-induced MYPT1 phosphorylation were resistant to the effects of insulin in diabetic GK VSMC. We also measured the isometric tension of intact and denuded GK aorta using a myograph and observed significantly impaired insulin-induced vasodilation. Adenovirus-mediated overexpression of constitutively active Akt in GK VSMC led to significantly improved insulin sensitivity in terms of counteracting ANG II-induced contractile signaling via MYPT1, myosin light chain dephosphorylation, and reduced iNOS expression, S-nitrosylation and survivin expression. We demonstrated for the first time the presence of Akt-independent iNOS expression in the GK diabetic model and that the defective insulin-induced vasodilation observed in the diabetic vasculature can be restored by the overexpression of active Akt, which advocates a novel therapeutic strategy for treating diabetes.