Rho-kinase as a molecular target for insulin resistance and hypertension.
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.
Kanda
Takeshi
T
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Wakino
Shu
S
Homma
Koichiro
K
Yoshioka
Kyoko
K
Tatematsu
Satoru
S
Hasegawa
Kazuhiro
K
Takamatsu
Ichiro
I
Sugano
Naoki
N
Hayashi
Koichi
K
Saruta
Takao
T
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000109:Acetylcholine; D000818:Animals; D001160:Arterioles / Q000187:drug effects; D002460:Cell Line; D005951:Glucose Tolerance Test; D006973:Hypertension / Q000188:drug therapy*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D018482:Muscle, Skeletal / Q000098:blood supply; D009599:Nitroprusside; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; C431085:hydroxyfasudil; D009599:Nitroprusside; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D000109:Acetylcholine; C049347:fasudil