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CARDIOVASCULAR

Increased RhoA/Rho-Kinase Signaling Mediates Spontaneous Tone in Aorta from Angiotensin II-Induced Hypertensive Rats

Department of Physiology (L.J., Z.Y., R.H.P.H., J.Y., J.D.I., R.C.W.) and Vascular Biology Center (X.Z., J.D.I., R.C.W.), Medical College of Georgia, Augusta, Georgia; and Department of Urology, The Johns Hopkins University, Baltimore, Maryland (L.J.)

Spontaneous tone in large arteries may contribute to the pathogenesis of hypertension. Reactive oxygen species and Ca²⁺ influx have been shown to stimulate the development of spontaneous tone in isolated aortic rings in several models of hypertensive rats. The aim of this study was to investigate the role of the RhoA/Rho-kinase signaling pathway in the development of spontaneous tone in angiotensin II-induced hypertension and to explore the underlying mechanisms of RhoA/Rho-kinase activation. Our results showed that spontaneous tone was greatly enhanced in endothelium-denuded aortic rings from angiotensin II-induced hypertensive rats compared with their normotensive counterparts (73 ± 5 versus 7 ± 3% of phenylephrine-induced maximal contraction, respectively). The Rho-kinase inhibitor (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide (Y-27632) (0.1-10 µM) concentration dependently inhibited spontaneous tone in aortic rings from angiotensin II-treated rats. NADPH oxidase inhibitors diphenylene iodonium and apocynin also significantly reduced spontaneous tone. Chronic angiotensin II treatment markedly increased RhoA protein expression (57%) but had no effect on Rho guanine nucleotide exchange factor mRNA or Rho-kinase protein expression levels. In endothelium-denuded rings from normotensive rats, angiotensin II (100 nM) increased RhoA membrane translocation and phosphorylation of the myosin light chain phosphatase target subunit, which were both blocked by the NADPH oxidase inhibitor diphenylene iodonium (10 µM). In conclusion, these data suggest that chronic treatment with angiotensin II leads to up-regulation of the RhoA/Rho-kinase pathway, contributing to spontaneous tone development in rat aorta. Increased NADPH oxidase-dependent reactive oxygen species may be one of the mechanisms mediating the RhoA/Rho-kinase activation.

Address correspondence to: Dr. Liming Jin, Department of Urology, 600 N. Wolfe St., The Johns Hopkins University, Baltimore, MD 21287. E-mail: ljin8{at}jhmi.edu

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