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Peroxynitrite inhibits the expression of G_i protein and adenylyl cyclase signaling in vascular smooth muscle cells

Department of Physiology, Faculty of Medicine, and Groupe de Recherche sur le Système Nerveux Autonome, University of Montreal, Montreal, Quebec, Canada

Submitted 18 July 2007 ; accepted in final form 20 November 2007

We previously showed that S-nitroso-N-acetylpenicillamine, a nitric oxide donor, decreased the levels and functions of G_i proteins by formation of peroxynitrite (ONOO^–) in vascular smooth muscle cells (VSMC). The present studies were undertaken to investigate whether ONOO^– can modulate the expression of G_i protein and associated adenylyl cyclase signaling in VSMC. Treatment of A-10 and aortic VSMC with ONOO^– for 24 h decreased the expression of G_i-2 and G_i-3, but not G_s, protein in a concentration-dependent manner; expression was restored toward control levels by ¹¹¹Mn-tetralis(benzoic acid porphyrin) and uric acid, but not by 1H[1,2,4]oxadiazole[4,3-a]quinoxaline-1-one (ODQ) and KT-5823. cGMP levels were increased by 50% and 150% by 0.1 and 0.5 mM ONOO^–, respectively, and attenuated toward control levels by ODQ. In addition, 0.5 mM ONOO^– attenuated the inhibition of adenylyl cyclase by ANG II and C-type atrial natriuretic peptide (C-ANP_4–23), as well as the inhibition of forskolin-stimulated adenylyl cyclase activity by GTPS, whereas, the G_s-mediated stimulations were augmented. In addition, 0.5 mM ONOO^– decreased phosphorylation of ERK1/2 and p38 MAP kinase and enhanced JNK phosphorylation but did not affect AKT1/3 phosphorylation. These results suggest that ONOO^– decreased the expression of G_i proteins and associated functions in VSMC through a cGMP-independent mechanism and may involve the MAP kinase signaling pathway.

G protein; mitogen-activated protein kinase

This article has been cited by other articles:

				Y. Li, M. Descorbeth, and M. B. Anand-Srivastava Role of oxidative stress in high glucose-induced decreased expression of Gi{alpha} proteins and adenylyl cyclase signaling in vascular smooth muscle cells Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2845 - H2854. [Abstract] [Full Text] [PDF]