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J. Biol. Chem., Vol. 282, Issue 1, 792-799, January 5, 2007

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Role of Reduced Lipoic Acid in the Redox Regulation of Mitochondrial Aldehyde Dehydrogenase (ALDH-2) Activity

IMPLICATIONS FOR MITOCHONDRIAL OXIDATIVE STRESS AND NITRATE TOLERANCE^*

Philip Wenzel¹, Ulrich Hink¹, Matthias Oelze, Swaantje Schuppan, Karin Schaeuble, Stefan Schildknecht^¶, Kwok K. Ho^||, Henry Weiner^||, Markus Bachschmid^¶, Thomas Münzel, and Andreas Daiber²

From the Department of Cardiology, 2nd Medical Clinic, Johannes Gutenberg University, University Hospital Mainz, Verfügungsgebäude 911, Obere Zahlbacher Strasse 63, 55101 Mainz, Germany, the Department of Biological Chemistry, University of Konstanz, 78457 Konstanz, Germany, the ^¶Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, and the ^||Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907-2063

Chronic therapy with nitroglycerin results in a rapid development of nitrate tolerance, which is associated with an increased production of reactive oxygen species. We have recently shown that mitochondria are an important source of nitroglycerin-induced oxidants and that the nitroglycerin-bioactivating mitochondrial aldehyde dehydrogenase is oxidatively inactivated in the setting of tolerance. Here we investigated the effect of various oxidants on aldehyde dehydrogenase activity and its restoration by dihydrolipoic acid. In vivo tolerance in Wistar rats was induced by infusion of nitroglycerin (6.6 µg/kg/min, 4 days). Vascular reactivity was measured by isometric tension studies of isolated aortic rings in response to nitroglycerin. Chronic nitroglycerin infusion lead to impaired vascular responses to nitroglycerin and decreased dehydrogenase activity, which was corrected by dihydrolipoic acid co-incubation. Superoxide, peroxynitrite, and nitroglycerin itself were highly efficient in inhibiting mitochondrial and yeast aldehyde dehydrogenase activity, which was restored by dithiol compounds such as dihydrolipoic acid and dithiothreitol. Hydrogen peroxide and nitric oxide were rather insensitive inhibitors. Our observations indicate that mitochondrial oxidative stress (especially superoxide and peroxynitrite) in response to organic nitrate treatment may inactivate aldehyde dehydrogenase thereby leading to nitrate tolerance. Glutathionylation obviously amplifies oxidative inactivation of the enzyme providing another regulatory pathway. Furthermore, the present data demonstrate that the mitochondrial dithiol compound dihydrolipoic acid restores mitochondrial aldehyde dehydrogenase activity via reduction of a disulfide at the active site and thereby improves nitrate tolerance.

Received for publication, July 7, 2006 , and in revised form, October 13, 2006.

^* This work was supported by the German Research Foundation (DFG, Grant SFB 553-C17 to T. M. and A. D.) and by the European Vascular Genomic Network, a Network of Excellence supported by the European Community's sixth Framework Program (Workpackages 1-3). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. I-XV, Table I, Extended Experimental Procedures, Extended Discussion, and additional references.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 49-6131-3933301; Fax: 49-6131-3933304; E-mail: andreas.daiber{at}bioredox.com.

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