title: Nitric oxide attenuates insulin- or IGF-I-stimulated aortic smooth muscle cell motility by decreasing H2O2 levels: essential role of cGMP.
abstract: Insulin and insulin-like growth factor I (IGF-I) both play important roles in vascular remodeling. Moreover, nitric oxide (NO) is well established as a counterregulatory agent that opposes the actions of several vascular agonists, in part by decreasing smooth muscle motility. We tested the hypothesis that NO blocks insulin or IGF-I-induced rat aortic smooth muscle cell motility via a mechanism involving the attenuation of agonist-induced elevation of hydrogen peroxide levels and cGMP as mediator. Insulin or IGF-I induced an increase of hydrogen peroxide levels and cell motility. Both effects were blocked by catalase or diphenyleneiodonium, indicating that hydrogen peroxide elevation is necessary for induction of cell motility. Two NO donors mimicked the effects of catalase, indicating that NO decreases cell motility by suppressing agonist-induced elevation of hydrogen peroxide. A cGMP analogue mimicked the effect of NO, whereas a guanyl cyclase inhibitor blocked the effect of NO on hydrogen peroxide levels, indicating that elevation of cGMP is both necessary and sufficient to account for the reduction of hydrogen peroxide levels. A NO donor as well as a cGMP analogue attenuated insulin-stimulated NADPH activity, indicating that NO decreases hydrogen peroxide levels by inhibiting the generation of superoxide, via a cGMP-mediated mechanism. Finally, exogenous hydrogen peroxide increased cell motility and reversed the inhibitory effect of cGMP. These results support the view that NO plays an antioxidant role via reduction of hydrogen peroxide in cultured rat aortic smooth muscle cells and that this effect is both necessary and sufficient to account for its capacity to decrease cell motility.
authors.affiliation: Dept. of Physiology, University of Tennessee Heath Science Center, Memphis, TN 38103, USA.
authors.forename: Daming
authors.initials: D
authors.lastname: Zhuang
authors.forename: Alice-Corina
authors.initials: AC
authors.lastname: Ceacareanu
authors.forename: Yi
authors.initials: Y
authors.lastname: Lin
authors.forename: Bogdan
authors.initials: B
authors.lastname: Ceacareanu
authors.forename: Madhulika
authors.initials: M
authors.lastname: Dixit
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Chapman
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Waters
authors.forename: Gadiparthi N
authors.initials: GN
authors.lastname: Rao
authors.forename: Aviv
authors.initials: A
authors.lastname: Hassid
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000378:metabolism; D001013:Aorta, Thoracic / Q000166:cytology; D002374:Catalase / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology; D016877:Oxidants / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000975:Antioxidants; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D010069:Oxadiazoles; D016877:Oxidants; D011518:Proto-Oncogene Proteins; D011810:Quinoxalines; D009569:Nitric Oxide; D007334:Insulin-Like Growth Factor I; D006861:Hydrogen Peroxide; D002374:Catalase; D019255:NADPH Oxidases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D006162:Guanylate Cyclase; D006152:Cyclic GMP