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Peroxide generation by p47^phox-Src activation of Nox2 has a key role in protein kinase C-induced arterial smooth muscle contraction

Departments of ¹Physiology, ²Biochemistry & Molecular Biology, and ³Pediatrics, New York Medical College, Valhalla, New York

Submitted 11 May 2008 ; accepted in final form 13 January 2009

Protein kinase C (PKC) stimulation of NAD(P)H oxidases (Nox) is an important component of multiple vascular disease processes; however, the relationship between oxidase activation and the regulation of vascular smooth muscle contraction by PKC remains poorly understood. Therefore, we examined the signaling cascade of PKC-elicited Nox activation and the role of superoxide and hydrogen peroxide in mediating PKC-induced vascular contraction. Endothelium-denuded bovine coronary arteries showed a PKC-dependent basal production of lucigenin (5 µM)-detected Nox oxidase-derived superoxide, which was stimulated fourfold by PKC activation with 10 µM phorbol 12,13-dibutyrate (PDBu). PDBu appeared to increase superoxide generation by Nox2 through both p47^phox and peroxide-dependent Src activation mechanisms based on the actions of inhibitors, properties of Src phosphorylation, and the loss of responses in aorta from mice deficient in Nox2 and p47^phox. The actions of inhibitors of contractile regulating mechanisms, scavengers of superoxide and peroxide, and responses in knockout mouse aortas suggest that a major component of the contraction elicited by PDBu appeared to be mediated through peroxide derived from Nox2 activation stimulating force generation through Rho kinase and calmodulin kinase-II mechanisms. Superoxide generated by PDBu also attenuated relaxation to nitroglycerin. Peroxide-derived from Nox2 activation by PKC appeared to be a major contributor to the thromboxane A₂ receptor agonist U46619 [GenBank] (100 nM)-elicited contraction of coronary arteries. Thus a p47^phox and Src kinase activation of peroxide production by Nox2 appears to be an important contributor to vascular contractile mechanisms mediated through activation of PKC.

hydrogen peroxide; NADPH oxidase; protein kinase C; Src kinases; coronary artery

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