HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 296/4/H1048    most recent 00491.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Gupte, S. A. Articles by Wolin, M. S. Search for Related Content PubMed PubMed Citation Articles by Gupte, S. A. Articles by Wolin, M. S.

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

This article has been cited by other articles:

				J. Yang, P. H. Lane, J. S. Pollock, and P. K Carmines PKC-dependent superoxide production by the renal medullary thick ascending limb from diabetic rats Am J Physiol Renal Physiol, November 1, 2009; 297(5): F1220 - F1228. [Abstract] [Full Text] [PDF]