Bioactivation of Nitroglycerin by Purified Mitochondrial and Cytosolic Aldehyde Dehydrogenases
| Autor: | Wing Ming Keung, Matteo Beretta, Alexander Kollau, Walter Goessler, Michael Russwurm, Kurt Schmidt, Bernd Mayer, Karl Gruber, Doris Koesling |
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| Rok vydání: | 2008 |
| Předmět: |
Vascular smooth muscle
Serum albumin Chloral Aldehyde dehydrogenase Biochemistry Aldehyde Dehydrogenase 1 Family Catalysis Gene Expression Regulation Enzymologic Muscle Smooth Vascular Nitric oxide Nitroglycerin chemistry.chemical_compound Cytosol Animals Humans Protein Isoforms Bovine serum albumin Cyclic GMP Molecular Biology Serum Albumin ALDH2 Enzyme Catalysis and Regulation biology Aldehyde Dehydrogenase Mitochondrial Retinal Dehydrogenase Cell Biology Aldehyde Dehydrogenase Mitochondria Isoenzymes chemistry cardiovascular system biology.protein Cattle circulatory and respiratory physiology |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| Popis: | 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 EC(50) values of 42 +/- 2.9 and 3.1 +/- 0.4 microm 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. |
| Databáze: | OpenAIRE |
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