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Role of oxidative stress in angiotensin II-induced enhanced expression of G_i proteins and adenylyl cyclase signaling in A10 vascular smooth muscle cells

Department of Physiology and Groupe de recherche sur le système nerveux autonome, Faculty of Medicine, University of Montreal, Montréal, Québec, Canada

Submitted 23 October 2006 ; accepted in final form 29 November 2006

We have previously reported that angiotensin II (ANG II) treatment of A10 vascular smooth muscle cells (VSMCs) increased inhibitory G proteins (G_i protein) expression and associated adenylyl cyclase signaling which was attributed to the enhanced MAP kinase activity. Since ANG II has been shown to increase oxidative stress, we investigated the role of oxidative stress in ANG II-induced enhanced expression of G_i proteins and examined the effects of antioxidants on ANG II-induced enhanced expression of G_i proteins and associated adenylyl cyclase signaling in A10 VSMCs. ANG II treatment of A10 VSMCs enhanced the production of O₂^– and the expression of Nox4 and P47^phox, different subunits of NADPH oxidase, which were attenuated toward control levels by diphenyleneiodonium (DPI). In addition, ANG II augmented the expression of G_i-2 and G_i-3 proteins in a concentration- and time-dependent manner; the maximal increase in the expression of G_i was observed at 1 to 2 h and at 0.1–1.0 µM. The enhanced expression of G_i-2 and G_i-3 proteins was restored to control levels by antioxidants such as N-acetyl-L-cysteine, -tocopherol, DPI, and apocynin. In addition, ANG II also enhanced the ERK1/2 phosphorylation that was restored to control levels by DPI. Furthermore, the inhibition of forskolin-stimulated adenylyl cyclase activity by low concentrations of 5'-O-(3-triotriphosphate) (receptor-independent G_i functions) and ANG II-, des(Glu¹⁸,Ser¹⁹,Glu²⁰,Leu²¹,Gly²²)atrial natriuretic peptide_4-23-NH₂ (natriuretic peptide receptor-C agonist), and oxotremorine-mediated inhibitions of adenylyl cyclase (receptor-dependent functions) that were augmented in ANG II-treated VSMCs was also restored to control levels by antioxidant treatments. In addition, G_s-mediated diminished stimulation of adenylyl cyclase by stimulatory hormones in ANG II-treated cells was also restored to control levels by DPI. These results suggest that ANG II-induced enhanced levels of G_i proteins and associated functions in VSMCs may be attributed to the ANG II-induced enhanced oxidative stress, which exerts its effects through mitogen-activated protein kinase signaling pathway.

G protein; mitogen-activated protein kinase; adenylyl cyclase

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