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J. Biol. Chem., Vol. 280, Issue 17, 16594-16600, April 29, 2005

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Xanthine Oxidase Catalyzes Anaerobic Transformation of Organic Nitrates to Nitric Oxide and Nitrosothiols

CHARACTERIZATION OF THIS MECHANISM AND THE LINK BETWEEN ORGANIC NITRATE AND GUANYLYL CYCLASE ACTIVATION^*

Haitao Li, Hongmei Cui, Xiaoping Liu, and Jay L. Zweier¶

From the Center for Biomedical Electron Paramagnetic Resonance Spectroscopy and Imaging, Davis Heart and Lung Research Institute and Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio 43210

Organic nitrates have been used clinically in the treatment of ischemic heart disease for more than a century. Recently, xanthine oxidase (XO) has been reported to catalyze organic nitrate reduction under anaerobic conditions, but questions remain regarding the initial precursor of nitric oxide (NO) and the link of organic nitrate to the activation of soluble guanylyl cyclase (sGC). To characterize the mechanism of XO-mediated biotransformation of organic nitrate, studies using electron paramagnetic resonance spectroscopy, chemiluminescence NO analyzer, NO electrode, and immunoassay were performed. The XO reducing substrates xanthine, NADH, and 2,3-dihydroxybenz-aldehyde triggered the reduction of organic nitrate to nitrite anion (). Studies of the pH dependence of nitrite formation indicated that XO-mediated organic nitrate reduction occurred via an acid-catalyzed mechanism. In the absence of thiols or ascorbate, no NO generation was detected from XO-mediated organic nitrate reduction; however, addition of L-cysteine or ascorbate triggered prominent NO generation. Studies suggested that organic nitrite (R-O-NO) is produced from XO-mediated organic nitrate reduction. Further reaction of organic nitrite with thiols or ascorbate leads to the generation of NO or nitrosothiols and thus stimulates the activation of sGC. Only flavin site XO inhibitors such as diphenyleneiodonium inhibited XO-mediated organic nitrate reduction and sGC activation, indicating that organic nitrate reduction occurs at the flavin site. Thus, organic nitrite is the initial product in the process of XO-mediated organic nitrate biotransformation and is the precursor of NO and nitrosothiols, serving as the link between organic nitrate and sGC activation.

Received for publication, October 20, 2004 , and in revised form, January 4, 2005.

^* This work was supported in part by National Institutes of Health Grants HL63744, HL65608, and HL38324. 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.

Supported in part by an American Heart Association scientist development award.

To whom correspondence may be addressed: 110G Davis Heart and Lung Research Institute, 473 West 12th Ave., Columbus, OH 43210-1252. E-mail: li-13{at}medctr.osu.edu. ¶ To whom correspondence may be addressed: 110G Davis Heart and Lung Research Institute, 473 West 12th Ave., Columbus, OH 43210-1252. E-mail: zweier-1{at}medctr.osu.edu.

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