Rho‐kinase as a molecular target for insulin resistance and hypertension

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Abstract
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‐α 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.
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  • Ministry of Science and Technology

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