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International Journal of Hypertension
Volume 2013, Article ID 842827, 9 pages
http://dx.doi.org/10.1155/2013/842827
Research Article

Strategies Aimed at Nox4 Oxidase Inhibition Employing Peptides from Nox4 B-Loop and C-Terminus and p22phox N-Terminus: An Elusive Target

1Vascular Medicine Institute, University of Pittsburgh, 12th Floor BST, 200 Lothrop Street, Pitsburgh, PA 15261, USA
2Department of Pharmacology & Chemical Biology, University of Pittsburgh, 13th Floor BST, 200 Lothrop Street, Pitsburgh, PA 15261, USA

Received 21 December 2012; Accepted 10 February 2013

Academic Editor: Nicolas Federico Renna

Copyright © 2013 Gábor Csányi and Patrick J. Pagano. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Although NADPH oxidase 4 (Nox4) is the most abundant Nox isoform in systemic vascular endothelial and smooth muscle cells, its function in the vascular tissue is not entirely known. The literature describes a pathophysiological role for Nox4 in cardiovascular disease; however, some studies have reported that it has a protective role. To date, specific Nox4 inhibitors are not available; hence, the development of a pharmacologic tool to assess Nox4’s pathophysiological role garners intense interest. In this study, we selected peptides corresponding to regions in the Nox4 oxidase complex critical to holoenzyme activity and postulated their utility as specific competitive inhibitors. Previous studies in our laboratory yielded selective inhibition of Nox2 using this strategy. We postulated that peptides mimicking the Nox4 B-loop and C-terminus and regions on inhibit Nox4 activity. To test our hypothesis, the inhibitory activity of Nox4 B-loop and C-terminal peptides as well as N-terminal peptides was assessed in a reconstituted Nox4 system. Our findings demonstrate that Nox4 inhibition is not achieved by preincubation with this comprehensive array of peptides derived from previously identified active regions. These findings suggest that Nox4 exists in a tightly assembled and active conformation which, unlike other Noxes, cannot be disrupted by conventional means.