ha-1100 and Insulin-Resistance

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.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Acetylcholine; Animals; Arterioles; Cell Line; Glucose Tolerance Test; Hypertension; Insulin; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Muscle, Skeletal; Nitroprusside; Protein Serine-Threonine Kinases; Protein Transport; Rats; Rats, Zucker; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction; Tumor Necrosis Factor-alpha