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This Article Full Text Full Text (PDF) All Versions of this Article: 294/6/H2845    most recent 91422.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Li, Y. Articles by Anand-Srivastava, M. B. PubMed PubMed Citation Articles by Li, Y. Articles by Anand-Srivastava, M. B.

Role of oxidative stress in high glucose-induced decreased expression of G_i proteins and adenylyl cyclase signaling in vascular smooth muscle cells

Department of Physiology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada

Submitted 7 December 2007 ; accepted in final form 23 April 2008

We have recently shown that aorta from streptozotocin (STZ)-induced diabetic rats and A10 vascular smooth muscle cells (VSMCs) exposed to high glucose exhibited decreased levels of inhibitory guanine nucleotide regulatory protein (G_i) proteins. In the present studies, we investigated the implication of oxidative stress in the hyperglycemia/diabetes-induced decreased expression of the G_i protein and adenylyl cyclase signaling in VSMCs by using antioxidants. The levels of G_i proteins were significantly decreased in A10 VSMCs exposed to high glucose and in aortic VSMCs from STZ-diabetic rats compared with control cells and were restored to control levels by antioxidants. In addition, ¹¹¹Mn-tetralis(benzoic acid porphyrin) and uric acid, scavengers of peroxynitrite, and N^G-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase but not catalase, also restored the high glucose-induced decreased expression of G_i proteins to the control levels in A10 VSMCs. Furthermore, the enhanced production of superoxide anion (O₂^–) and increased activity of NADPH oxidase in these cells were also restored to control levels by diphenyleneiodonium, an inhibitor of NADPH oxidase. In addition, the diminished inhibition of adenylyl cyclase activity by inhibitory hormones and forskolin-stimulated adenylyl cyclase activity by low concentrations of GTPS as well as the enhanced stimulation of adenylyl cyclase by stimulatory agonists in hyperglycemic cells were restored to control levels by antioxidant treatments. These results suggest that high glucose-induced decreased levels of G_i proteins and associated signaling in A10 VSMCs may be attributed to the enhanced oxidative stress due to augmented levels of peroxynitrite and not to H₂O₂.

G proteins; antioxidants; inhibitory guanine nucleotide regulatory protein