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J. Biol. Chem., Vol. 279, Issue 23, 24493-24497, June 4, 2004

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Reoxygenation-induced Constriction in Murine Coronary Arteries

THE ROLE OF ENDOTHELIAL NADPH OXIDASE (gp91^phox) AND INTRACELLULAR SUPEROXIDE^*

John Q. Liu, Igor N. Zelko, and Rodney J. Folz

From the Departments of Medicine and Cell Biology, Division of Pulmonary, Allergy, and Critical Care, Duke University Medical Center, Durham, North Carolina 27710

Previous work suggests that superoxide mediates hypoxia/reoxygenation (H/R)-induced constriction of isolated mouse coronary arteries (CA). To determine the source of superoxide overproduction during H/R we studied CA obtained from transgenic (Tg) mice overexpressing human CuZn-superoxide dismutase (SOD) and mice lacking gp91^phox using an in vitro vascular ring bioassay. We found that under normoxic conditions CA isolated from wild type (wt) mice, CuZn-SOD Tg mice and gp91^phox knock-out mice had similar contractile responses to U46619 and hypoxia and similar dilation responses to acetylcholine. In wt CA, 30 min of hypoxia (1% O₂) followed by reoxygenation (16% O₂) resulted in further coronary vasoconstriction (internal diameter from 105 ± 11 to 84.5 ± 17.9 µm), whereas this response was completely blocked in both CuZn-SOD Tg and gp91^phox knock-out CA (104.3 ± 10.5 to 120.7 ± 14 µm and 143.3 ± 15.3 to 172.7 ± 12.5 µm, respectively, p < 0.01). Furthermore, we show that H/R enhances the generation of superoxide radicals in wt CA (25.8 ± 0.7 relative light units per second (RLU/s)), whereas CuZn-SOD Tg CA (12.2 ± 0.8 RLU/s, p < 0.01) and gp91^phox CA (12.5 ± 0.9 RLU/s, p < 0.01) show reduced levels. These results demonstrate that H/R-induced vasoconstriction is mediated by intracellular superoxide overproduction via endothelial NADPH oxidase gp91^phox. Therefore, increasing endogenous levels of CuZn-SOD in CA may provide a novel cardioprotective strategy for maintaining coronary perfusion under conditions of H/R.

Received for publication, March 16, 2004 , and in revised form, March 31, 2004.

^* This study was supported in part by American Heart Association (Mid-Atlantic Affiliates) Beginning Grant-in-aid 9960236U (to J. Q. L.) and National Institutes of Health Grant R01 HL-64894 (to R. J. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Division of Pulmonary, Allergy, and Critical Care, Dept. of Medicine, Duke University Medical Center, Box 2620, Rm. 341 MSRB, Durham, NC 27710. Tel.: 919-684-2719; Fax: 919-681-8936; E-mail: john.liu{at}duke.edu.

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