s-nitro-n-acetylpenicillamine and Diabetes-Mellitus--Type-2

Hyperinsulinemia is a significant risk factor for the pathogenesis of vascular disease. Protein tyrosine phosphatase 1B (PTP1B) has been recognized as a modulator of insulin signaling in nonvascular cells, and we have recently reported that NO increases the activity of PTP1B in rat vascular smooth muscle cells. In the present study, we tested the hypothesis that NO attenuates insulin-stimulated cell motility via a PTP1B-mediated mechanism involving downregulation of insulin signal transduction.. Treatment of primary aortic smooth muscle cells from newborn rats with the NO donor S-nitroso-N-acetylpenicillamine reduced cell motility, tyrosine phosphorylation levels of insulin receptor beta subunit and insulin receptor substrate-1, and extracellular signal-regulated kinase activity. Overexpression of wild-type PTP1B via an adenoviral vector blocked the capacity of insulin to stimulate cell motility and insulin receptor phosphorylation, whereas expression of a dominant-negative mutant of PTP1B attenuated the capacity of NO to decrease cell motility.. Our findings indicate that activation of PTP1B is necessary and sufficient to account for the capacity of NO to decrease insulin-stimulated signal transduction and cell motility in cultured aortic smooth muscle cells. The results could explain the capacity of NO to oppose neointima formation in states of hyperinsulinemia.

Topics: Animals; Animals, Newborn; Aorta, Thoracic; Butadienes; Cell Communication; Cell Movement; Cells, Cultured; Diabetes Mellitus, Type 2; Drug Synergism; Enzyme Inhibitors; Female; Insulin; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Muscle, Smooth, Vascular; Mutation; Nitric Oxide; Nitric Oxide Donors; Nitriles; Penicillamine; Phosphotyrosine; Protein Serine-Threonine Kinases; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatase, Non-Receptor Type 12; Protein Tyrosine Phosphatases; Rats; Rats, Sprague-Dawley; Receptor, Insulin; Recombinant Proteins; Signal Transduction; src Homology Domains