Rho-kinase as a molecular target for insulin resistance and hypertension
Rho-kinase as a molecular target for insulin resistance and hypertension
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DOI：
10.1096/fj.05-4197fje
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发表时间：
2005-11-01
期刊：
影响因子：
4.8
通讯作者：
Saruta, T
中科院分区：
文献类型：
--
作者：
Kanda, T;Wakino, S;Saruta, T
rho激酶在高血压中发挥重要作用，据报道，在培养的血管平滑肌细胞中，rho激酶通过胰岛素受体底物-1 （IRS-1）的丝氨酸磷酸化干扰胰岛素信号传导。因此，我们研究了rho激酶在Zucker肥胖大鼠胰岛素抵抗发展中的作用。在Zucker肥胖大鼠骨骼肌和主动脉组织中观察到RhoA/ rho激酶的活化。法舒地尔（一种rho激酶抑制剂）长期抑制rho激酶4周，不仅降低血压，而且纠正葡萄糖和脂质代谢，改善IRS-1丝氨酸磷酸化和骨骼肌胰岛素信号传导。用CCD视频显微镜直接观察骨骼肌小动脉，结果显示乙酰胆碱和硝普钠诱导的血管舒张功能减弱，经法舒地尔治疗后恢复。此外，法舒地尔和Y-27632均可阻止胰岛素和/或肿瘤坏死因子- α在骨骼肌细胞中诱导的IRS-1丝氨酸磷酸化。总的来说，rho激酶负责胰岛素信号的损伤，并可能构成胰岛素抵抗中代谢和血流动力学异常之间的关键介质。
Rho-kinase plays an important role in hypertension and is reported to interfere with insulin signaling through serine phosphorylation of insulin receptor substrate-1 (IRS-1) in cultured vascular smooth muscle cells. We therefore examined the role of Rho-kinase in the development of insulin resistance in Zucker obese rats. In skeletal muscles and aortic tissues of Zucker obese rats, activation of RhoA/Rho-kinase was observed. Long-term Rho-kinase inhibition by 4 wk treatment with fasudil (a Rho-kinase inhibitor) not only reduced blood pressure but corrected glucose and lipid metabolism, with improvement in serine phosphorylation of IRS-1 and insulin signaling in skeletal muscles. Direct visualization of skeletal muscle arterioles with an intravital CCD videomicroscope demonstrated that both acetylcholine- and sodium nitroprusside-induced vasodilations were blunted, which were restored by the fasudil treatment. Furthermore, both fasudil and Y-27632 prevented the serine phosphorylation of IRS-1 induced by insulin and/or tumor necrosis factor-alpha in skeletal muscle cells. Collectively, Rho-kinase is responsible for the impairment of insulin signaling and may constitute a critical mediator linking between metabolic and hemodynamic abnormalities in insulin resistance.