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Originally published In Press as doi:10.1074/jbc.M801182200 on May 1, 2008

J. Biol. Chem., Vol. 283, Issue 26, 17873-17880, June 27, 2008
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Bioactivation of Nitroglycerin by Purified Mitochondrial and Cytosolic Aldehyde Dehydrogenases*

Matteo Beretta{ddagger}, Karl Gruber§, Alexander Kollau{ddagger}, Michael Russwurm, Doris Koesling, Walter Goessler§, Wing Ming Keung||, Kurt Schmidt{ddagger}, and Bernd Mayer{ddagger}1

From the Departments of {ddagger}Pharmacology and Toxicology and §Chemistry, Karl-Franzens-Universität Graz, A-8010 Graz, Austria, the Department of Pharmacology and Toxicology, Ruhr-Universität Bochum, D-44780 Bochum, Germany, and the ||Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115

Metabolism of nitroglycerin (GTN) to 1,2-glycerol dinitrate (GDN) and nitrite by mitochondrial aldehyde dehydrogenase (ALDH2) is essentially involved in GTN bioactivation resulting in cyclic GMP-mediated vascular relaxation. The link between nitrite formation and activation of soluble guanylate cyclase (sGC) is still unclear. To test the hypothesis that the ALDH2 reaction is sufficient for GTN bioactivation, we measured GTN-induced formation of cGMP by purified sGC in the presence of purified ALDH2 and used a Clark-type electrode to probe for nitric oxide (NO) formation. In addition, we studied whether GTN bioactivation is a specific feature of ALDH2 or is also catalyzed by the cytosolic isoform (ALDH1). Purified ALDH1 and ALDH2 metabolized GTN to 1,2- and 1,3-GDN with predominant formation of the 1,2-isomer that was inhibited by chloral hydrate (ALDH1 and ALDH2) and daidzin (ALDH2). GTN had no effect on sGC activity in the presence of bovine serum albumin but caused pronounced cGMP accumulation in the presence of ALDH1 or ALDH2. The effects of the ALDH isoforms were dependent on the amount of added protein and, like 1,2-GDN formation, were sensitive to ALDH inhibitors. GTN caused biphasic sGC activation with apparent EC50 values of 42 ± 2.9 and 3.1 ± 0.4 µM in the presence of ALDH1 and ALDH2, respectively. Incubation of ALDH1 or ALDH2 with GTN resulted in sustained, chloral hydrate-sensitive formation of NO. These data may explain the coupling of ALDH2-catalyzed GTN metabolism to sGC activation in vascular smooth muscle.


Received for publication, February 13, 2008 , and in revised form, April 30, 2008.

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* This work was supported by Grants W901 DK Molecular Enzymology, P16690 [GenBank] , and P20669 [GenBank] from the Fonds zur Föderung der Wissenschaftlichen Forschung in Austria (to B. M.), Deutsche Forschungsgemeinschaft Grant KO1157/4-1 (to D. K. and M. R.), and the Endowment for Research in Human Biology, Boston, Massachusetts (to W. M. K.). 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.

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1 To whom correspondence should be addressed: Dept. of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Universitätsplatz 2, A-8010 Graz, Austria. Tel.: 43-316-380-5567; Fax: 43-316-380-9890; E-mail: mayer{at}uni-graz.at.


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