Hyperinsulinemia-induced vascular smooth muscle cell (VSMC) migration and proliferation is mediated by converging mechanisms of mitochondrial dysfunction and oxidative stress
Hyperinsulinemia-induced vascular smooth muscle cell (VSMC) migration and proliferation is mediated by converging mechanisms of mitochondrial dysfunction and oxidative stress
复制标题
DOI：
10.1007/s11010-012-1478-5
复制
发表时间：
2013-01-01
影响因子：
4.3
通讯作者：
Balasubramanyam, Muthuswamy
中科院分区：
文献类型：
--
作者：
Abhijit, Shiny;Bhaskaran, Regin;Balasubramanyam, Muthuswamy
动脉粥样硬化是糖尿病的主要并发症之一，涉及内皮功能障碍、基质改变，最重要的是血管平滑肌细胞（vsmc）的迁移和增殖。虽然已知高血糖和高胰岛素血症有助于动脉粥样硬化，但对介导vsmc中有害的高胰岛素效应的特定细胞信号通路知之甚少。因此，我们研究了高胰岛素诱导VSMCs迁移和增殖的细胞机制。用胰岛素（100 nM）治疗VSMCs 6天，并进行各种生理和分子研究。高胰岛素血症的VSMCs表现出迁移和增殖的增加，这与氧化应激[NADPH氧化酶活性增加，NADPH氧化酶1 mRNA表达增加，活性氧（ROS）产生]，线粒体生理改变（膜去极化，线粒体质量减少，线粒体ROS增加），线粒体生物发生相关基因(mitofusin 1, mitofusin 2，动力蛋白相关蛋白1，过氧化物酶体增殖物激活受体γ辅助激活因子1- α，过氧化物酶体增殖物激活受体γ辅助激活因子1- β，核呼吸因子1和解偶联蛋白2)，并增加Akt磷酸化。二苯乙烯酮是一种已知的NADPH氧化酶抑制剂，可显著抑制VSMCs的迁移和增殖，并使上述生理和分子扰动正常化。本研究提示高胰岛素血症下线粒体功能障碍和氧化应激之间存在似是而非的联系，并强调对抗线粒体功能障碍和氧化应激是动脉粥样硬化的一种新的治疗策略。
Atherosclerosis is one of the major complications of diabetes and involves endothelial dysfunction, matrix alteration, and most importantly migration and proliferation of vascular smooth muscle cells (VSMCs). Although hyperglycemia and hyperinsulinemia are known to contribute to atherosclerosis, little is known about the specific cellular signaling pathways that mediate the detrimental hyperinsulinemic effects in VSMCs. Therefore, we investigated the cellular mechanisms of hyperinsulinemia-induced migration and proliferation of VSMCs. VSMCs were treated with insulin (100 nM) for 6 days and subjected to various physiological and molecular investigations. VSMCs subjected to hyperinsulinemia exhibited increased migration and proliferation, and this is paralleled by oxidative stress [increased NADPH oxidase activity, NADPH oxidase 1 mRNA expression, and reactive oxygen species (ROS) generation], alterations in mitochondrial physiology (membrane depolarization, decreased mitochondrial mass, and increased mitochondrial ROS), changes in mitochondrial biogenesis-related genes (mitofusin 1, mitofusin 2, dynamin-related protein 1, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, peroxisome proliferator-activated receptor gamma coactivator 1-beta, nuclear respiratory factor 1, and uncoupling protein 2), and increased Akt phosphorylation. Diphenyleneiodonium, a known NADPH oxidase inhibitor significantly inhibited migration and proliferation of VSMCs and normalized all the above physiological and molecular perturbations. This study suggests a plausible crosstalk between mitochondrial dysfunction and oxidative stress under hyperinsulinemia and emphasizes counteracting mitochondrial dysfunction and oxidative stress as a novel therapeutic strategy for atherosclerosis.