NO attenuates insulin signaling and motility in aortic smooth muscle cells via protein tyrosine phosphatase 1B-mediated mechanism.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Physiology and Vascular Biology Center, University of Tennessee Health Science Center, Memphis 38163, USA.
Nair
N
Sreejayan
Yi
Y
Lin
Aviv
A
Hassid
D000818:Animals; D000831:Animals, Newborn; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D002070:Butadienes / Q000494:pharmacology; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007328:Insulin / Q000378:metabolism / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D009154:Mutation; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019000:Phosphotyrosine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018909:src Homology Domains / Q000187:drug effects / Q000502:physiology
D002070:Butadienes; D004791:Enzyme Inhibitors; D007328:Insulin; D020030:Nitric Oxide Donors; D009570:Nitriles; D011994:Recombinant Proteins; C110881:S-nitro-N-acetylpenicillamine; C113580:U 0126; D019000:Phosphotyrosine; D009569:Nitric Oxide; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12; D017027:Protein Tyrosine Phosphatases; C516610:Ptpn1 protein, rat; C516740:Ptpn12 protein, rat; D010396:Penicillamine