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Essential role of protein kinase G and decreased cytoplasmic Ca²⁺ levels in NO-induced inhibition of rat aortic smooth muscle cell motility

¹Department of Physiology and ²Vascular Biology Center, University of Tennessee Health Sciences Center, Memphis, Tennessee

Submitted 7 October 2004 ; accepted in final form 29 November 2004

Hyperinsulinemia is a major risk factor for the development of vascular disease. We have reported that insulin increases the motility of vascular smooth muscle cells via a hydrogen peroxide-mediated mechanism and that nitric oxide (NO) attenuates insulin-induced motility via a cGMP-mediated mechanism. Events downstream of cGMP elevation have not yet been investigated. The aim of our study was to test the hypothesis that antimotogenic effects of NO and cGMP in cultured rat aortic smooth muscle cells are mediated via PKG, followed by reduction of cytoplasmic Ca²⁺ levels and increased protein tyrosine phosphatase-proline, glutamate, serine, and threonine activity, leading to suppression of agonist-induced elevation of hydrogen peroxide levels and cell motility. Treatment of primary cultures with adenovirus expressing PKG-1 mimicked NO-induced inhibition of insulin-elicited hydrogen peroxide elevation and cell motility, whereas treatment with the pharmacological PKG inhibitor Rp-8-bromo-3',5'-cyclic monophosphorothioate (Rp-8-Br-cGMPS) rescued the stimulatory effects of insulin that were suppressed by NO donor. Treatment of cells with insulin failed to increase cytoplasmic Ca²⁺ levels, whereas NO donor decreased cytoplasmic Ca²⁺ levels in the presence or absence of insulin. Treatment of cells with the Ca²⁺ chelator BAPTA mimicked the effects of PKG and the NO donor and increased the activity of PTP-PEST. Finally, treatment with a dominant negative allele of PTP-PEST reversed the inhibitory effect of BAPTA on cell motility and hydrogen peroxide elevation. We conclude that NO-induced inhibition of cell motility occurs via PKG-mediated reduction of basal cytoplasmic Ca²⁺ levels, followed by increased PTP-PEST activity, leading to decreased hydrogen peroxide levels and reduced cell motility.

calcium chelator; protein tyrosine phosphatase-proline; glutamate; serine; and threonine; insulin; hydrogen peroxide

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