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on October 5, 2006

Arteriosclerosis, Thrombosis, and Vascular Biology. 2006
Published online before print October 5, 2006, doi: 10.1161/01.ATV.0000249394.94588.82
A more recent version of this article appeared on December 1, 2006
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Submitted on June 23, 2006
Accepted on September 15, 2006

Uncoupling of Endothelial Nitric Oxidase Synthase by Hypochlorous Acid. Role of NAD(P)H Oxidase-Derived Superoxide and Peroxynitrite

Jian Xu ; Zhonglin Xie ; Richard Reece ; David Pimental ; and Ming-Hui Zou *

From the Section of Endocrinology and Diabetes, Department of Medicine (J.X., Z.X., R.R., M.-H.Z.), University of Oklahoma Health Sciences Center, Oklahoma City; and the Division of Cardiology, Department of Medicine (D.P., M.-H.Z.), Boston University School of Medicine, Boston, Mass.

* To whom correspondence should be addressed. E-mail: ming-hui-zou{at}ouhsc.edu.

Objective--The aim of the present study is to determine whether hypochlorous acid (HOCl), the major oxidant of leukocyte-derived myeloperoxidase (MPO), oxidizes the zinc-thiolate center of endothelial nitric oxide synthase (eNOS) and uncouples the enzyme.

Methods and Results--Exposure of purified recombinant eNOS to HOCl (≥100 µmol/L) released zinc and disrupted the enzyme-active eNOS dimers. In parallel with increased detections of both O2·- and ONOO-, clinically relevant concentrations of HOCl disrupted eNOS dimers in cultured human umbilical vein endothelial cells (HUVEC) at concentration 10- to 100-fold lower than those required for recombinant eNOS. In HUVEC, HOCl increased the translocation of both p67phox and p47phox of NAD(P)H oxidase and the phosphorylation of atypical protein kinase C-{zeta}. Further, genetic or pharmacological inhibition of either NAD(P)H oxidase-derived O2·- or PKC-{zeta} or NOS abolished the effects of HOCl on eNOS dimers. Consistently, HOCl increased both O2·- and ONOO- and eNOS dimer oxidation in isolated mouse aortas from C57BL/6 but less in those of gp91phox knock-out mice. Finally, in human carotid atherosclerotic arteries, eNOS predominantly existed as monomers in parallel with increased staining of both MPO and 3-nitrotyrosine.

Conclusions--We conclude that HOCl uncouples eNOS by ONOO- generated from PKC-{zeta}-dependent NAD(P)H oxidase.
Key words: hypochlorite • endothelial dysfunction • NAD(P)H oxidase • peroxynitrite


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