Insulin-mediated upregulation of K(Ca)3.1 channels promotes cell migration and proliferation in rat vascular smooth muscle.
Insulin-mediated upregulation of K(Ca)3.1 channels promotes cell migration and proliferation in rat vascular smooth muscle.
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DOI：
10.1016/j.yjmcc.2011.03.014
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发表时间：
2011-07
影响因子：
5
通讯作者：
Xing-Li Su;Yan Wang;Wei Zhang;Limei Zhao;Gui-Rong Li;Xiu-Ling Deng
中科院分区：
文献类型：
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作者：
Xing-Li Su;Yan Wang;Wei Zhang;Limei Zhao;Gui-Rong Li;Xiu-Ling Deng
在2型糖尿病中，各种血管疾病（如动脉粥样硬化）发病机制的详细分子机制尚未完全了解。本研究旨在探讨胰岛素是否调节KCa3.1通道，并参与2型糖尿病血管病变。采用实验性胰岛素抵抗2型糖尿病大鼠模型，检测主动脉壁的病理变化，并采用体外培养的血管平滑肌细胞（VSMCs），从分子生物学和电生理学角度研究胰岛素对KCa 3.1通道的调节及其在细胞迁移和增殖中的作用。2型糖尿病大鼠主动脉壁出现早期病理改变，KCa 3.1通道表达增加。在培养的VSMCs中，经胰岛素处理后，KCa 3.1通道的mRNA、蛋白水平和电流密度均显著增强，而经ERK 1/2抑制剂PD98059处理的细胞中，这种效应被抵消，但p38-MAPK抑制剂SB 203580处理的细胞中没有这种效应。此外，胰岛素刺激培养的VSMCs的细胞迁移和增殖，并且在用KCa3.1阻断剂TRAM-34或PD98059处理的细胞中，而不是SB203580，这种作用完全逆转。这些结果证明了胰岛素通过刺激ERK 1/2磷酸化增加KCa 3.1通道的表达，从而促进VSMC的迁移和增殖的新信息，这可能在2型糖尿病血管病变的发展中至少起部分作用。
The detailed molecular mechanisms underlying pathogenesis of various vascular diseases such as atherosclerosis are not fully understood in type-2 diabetes. The present study was designed to investigate whether insulin regulates KCa3.1 channels and participates in vasculopathy in type-2 diabetes. A rat model with experimental insulin-resistant type-2 diabetes was used for detecting pathological changes in the aorta wall, and cultured vascular smooth muscle cells (VSMCs) were employed to investigate the regulation of KCa3.1 channels by insulin and roles of KCa3.1 channels in cell migration and proliferation using molecular biology and electrophysiology. Early pathological changes were observed and expression of KCa3.1 channels increased in the aorta wall of the type 2 diabetic rats. KCa3.1 channel mRNA, protein levels and current density were greatly enhanced in cultured VSMCs treated with insulin, and the effects were countered in the cells treated with the ERK1/2 inhibitor PD98059, but not the p38-MAPK inhibitor SB203580. In addition, insulin stimulated cell migration and proliferation in cultured VSMCs, and the effects were fully reversed in the cells treated with the KCa3.1 blocker TRAM-34 or PD98059, but not SB203580. These results demonstrate the novel information that insulin increases expression of KCa3.1 channels by stimulating ERK1/2 phosphorylation thereby promoting migration and proliferation of VSMCs, which likely play at least a partial role in the development of vasculopathy in type-2 diabetes.