on August 26, 2004
Published online before print August 26, 2004, doi: 10.1161/01.ATV.0000143388.20994.fa
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Submitted on July 6, 2004
Accepted on August 16, 2004
Hypochlorous Acid Impairs Endothelium-Derived Nitric Oxide Bioactivity Through a Superoxide-Dependent Mechanism
Roland Stocker ;
From the Evans Memorial Department of Medicine and Whitaker Cardiovascular Institute (R.S., A.H., E.J., T.W., S.R.T., J.F.K.), Boston University School of Medicine, Mass; and the Centre for Vascular Research (R.S., J.Y.H., S.R.T.), University of New South Wales, Sydney, and the Department of Haematology, Prince of Wales Hospital, Randwick, Australia.
* To whom correspondence should be addressed. E-mail: jkeaney{at}bu.edu.
Objective--To determine how hypochlorous acid (HOCl), the principal product of myeloperoxidase, modulates vascular function.
Methods and Results--Rabbit arterial rings exposed to HOCl (0 to 500 µmol/L) exhibited dose- and time-dependent impairment of endothelium-dependent arterial relaxation to acetylcholine and A23187, but not the NO donor, diethylamine NONOate, suggesting that HOCl targets the endothelium. This effect was not because of cytotoxicity, as HOCl treatment produced no significant change in endothelial cell morphology or lactate dehydrogenase release. We observed HOCl-mediated endothelial cell protein oxidation by immunoreactivity to HOP-1, a monoclonal antibody specific for HOCl-oxidized protein. In support of this notion, known HOCl scavengers, such as methionine and N-acetylcysteine, partially preserved endothelium-derived NO bioactivity in response to HOCl. In an unanticipated observation, HOCl-mediated impairment of NO bioactivity was prevented by manganese superoxide dismutase in a manner dependent on its enzymatic activity. Finally, we found that HOCl reduced endothelial nitric oxide synthase dimer stability, an effect that was also inhibited by superoxide dismutase.
Conclusions--Taken together, these data indicate that HOCl imparts a defect in endothelial NO production due to a superoxide-dependent reduction in endothelial nitric oxide synthase dimer stability. These data provide another mechanism whereby myeloperoxidase-derived oxidants can contribute to the impairment of NO bioactivity that is characteristic of atherosclerosis.
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