Impaired insulin-stimulated myosin phosphatase Rho-interacting protein signaling in diabetic Goto-Kakizaki vascular smooth muscle cells
Impaired insulin-stimulated myosin phosphatase Rho-interacting protein signaling in diabetic Goto-Kakizaki vascular smooth muscle cells
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DOI：
10.1152/ajpcell.00254.2011
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发表时间：
2012-05-01
影响因子：
5.5
通讯作者：
Ragolia, Louis
中科院分区：
文献类型：
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作者：
Lee, Jin Hee;Palaia, Thomas;Ragolia, Louis
李JH，Palaia T，Ragolia L.糖尿病Goto-Kakizaki血管平滑肌细胞中胰岛素刺激的肌球蛋白磷酸酶Rho相互作用蛋白信号传导受损美国生理学杂志细胞生理学302：C1371-C1381，2012年。首次发表于2012年2月8日; doi：10.1152/ajpcell.00254.2011。与2型糖尿病相关的胰岛素抵抗导致血管舒张受损，因此导致糖尿病中观察到的高血压发病率增加。在这项研究中，我们研究了胰岛素对肌球蛋白磷酸酶（MYPT 1）的肌球蛋白结合亚基与肌球蛋白磷酸酶Rho相互作用蛋白（MRIP）的关联的作用，MRIP是一种相对新颖的肌球蛋白磷酸酶复合物，可直接结合血管平滑肌细胞（VSMC）中的RhoA。通过一系列的分子和细胞研究，我们研究了胰岛素是否刺激MRIP与MYPT 1的结合，并比较了从Wistar-Kyoto（WKY）对照和Goto-Kakizaki（GK）糖尿病大鼠分离的VSMCs产生的结果。我们首次证明胰岛素刺激MRIP与MYPT 1的结合具有剂量和时间依赖性，这一点通过免疫沉淀法确定，这意味着MRIP通过MYPT 1相互作用在胰岛素诱导的血管舒张信号传导中具有调节作用。2型糖尿病GK模型的VSMCs具有胰岛素诱导的MRIP/MYPT 1结合受损以及MRIP表达降低。腺病毒介导的GK VSMCs中MRIP的过表达导致胰岛素刺激的MRIP/MYPT 1结合显著改善。最后，胰岛素刺激的MRIP易位的应力纤维，这是观察到在控制VSMCs，GK VSMCs受损。我们认为，在GK糖尿病模型中，MRIP的表达受损，因此胰岛素刺激的MRIP/MYPT 1相关性降低，可能有助于在糖尿病血管系统中观察到的胰岛素介导的血管舒张受损，并为治疗2型糖尿病提供了一种新的治疗策略。
Lee JH, Palaia T, Ragolia L. Impaired insulin-stimulated myosin phosphatase Rho-interacting protein signaling in diabetic Goto-Kakizaki vascular smooth muscle cells. Am J Physiol Cell Physiol 302: C1371-C1381, 2012. First published February 8, 2012; doi:10.1152/ajpcell.00254.2011.-Insulin resistance associated with Type 2 diabetes contributes to impaired vasorelaxation and therefore contributes to the enhanced incidence of hypertension observed in diabetes. In this study, we examined the role of insulin on the association of the myosin-binding subunit of myosin phosphatase (MYPT1) to myosin phosphatase Rho-interacting protein (MRIP), a relatively novel member of the myosin phosphatase complex that directly binds RhoA in vascular smooth muscle cells (VSMCs). Through a series of molecular and cellular studies, we investigated whether insulin stimulates the binding of MRIP to MYPT1 and compared the results generated from VSMCs isolated from both Wistar-Kyoto (WKY) control and Goto-Kakizaki (GK) diabetic rats. We demonstrate for the first time that insulin stimulates the binding of MRIP to MYPT1 in a dose-and time-dependent manner, as determined by immunoprecipitation, implying a regulatory role for MRIP in insulin-induced vasodilation signaling via MYPT1 interaction. VSMCs from GK model of Type 2 diabetes had impaired insulin-induced MRIP/MYPT1 binding as well as reduced MRIP expression. Adenovirus-mediated overexpression of MRIP in GK VSMCs led to significantly improved insulin-stimulated MRIP/MYPT1 binding. Finally, insulin-stimulated MRIP translocation out of stress fibers, which was observed in control VSMCs, was impaired in GK VSMCs. We believe the impaired expression of MRIP, and therefore decreased insulin-stimulated MRIP/MYPT1 association, in the GK diabetic model may contribute to the impaired insulin-mediated vasodilation observed in the diabetic vasculature and provides a novel therapeutic strategy for the treatment of Type 2 diabetes.