Increased RhoA/Rho-Kinase Signaling Mediates Spontaneous Tone in Aorta from Angiotensin II-Induced Hypertensive Rats
- 28 March 2006
- journal article
- research article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in The Journal of pharmacology and experimental therapeutics
- Vol. 318 (1), 288-295
- https://doi.org/10.1124/jpet.105.100735
Abstract
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.Keywords
This publication has 25 references indexed in Scilit:
- PI3-Kinase Upregulation and Involvement in Spontaneous Tone in Arteries From DOCA-Salt RatsHypertension, 2004
- Role of oxidative stress and nitric oxide in regulation of spontaneous tone in aorta of DOCA-salt hypertensive ratsBritish Journal of Pharmacology, 2004
- Phosphoinositide 3-Kinase Mediates Enhanced Spontaneous and Agonist-Induced Contraction in Aorta of Deoxycorticosterone Acetate-Salt Hypertensive RatsCirculation Research, 2002
- Angiotensin II-induced cardiac hypertrophy and hypertension are attenuated by epidermal growth factor receptor antisense.Circulation, 2002
- Possible Involvement of Rho-Kinase in the Pathogenesis of Hypertension in HumansHypertension, 2001
- Role for G 12 /G 13 in Agonist-Induced Vascular Smooth Muscle Cell ContractionCirculation Research, 2000
- NAD(P)H OxidaseCirculation Research, 2000
- Differential Involvement of Gα12 and Gα13 in Receptor-mediated Stress Fiber FormationPublished by Elsevier BV ,1999
- Paracrine Role of Adventitial Superoxide Anion in Mediating Spontaneous Tone of the Isolated Rat Aorta in Angiotensin II-Induced HypertensionHypertension, 1999
- Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells.Circulation Research, 1994