Aldehyde dehydrogenase-independent bioactivation of nitroglycerin in porcine and bovine blood vessels.
Bottom Line: ALDH2 mRNA expression and the rates of GTN denitration were similarly low, excluding a significant contribution of ALDH2 to the bioactivation of GTN in these vessels.Attempts to identify the responsible pathway with enzyme inhibitors did not provide conclusive evidence for the involvement of ALDH3A1, cytochrome P450, or GSH-S-transferase.If present in the human vasculature, this pathway might contribute to the therapeutic effects of organic nitrates that are not metabolized by ALDH2.
Affiliation: Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Austria.Show MeSH
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Mentions: To shed light on this issue, we studied ALDH2 expression in these blood vessels by quantitative immunoblotting using human ALDH2 as a standard protein. As shown in Fig. 4A, homogenates of rat aorta contained 4.6 ± 0.65 ng of ALDH2 per μg of total protein. Expression of ALDH2 was much lower in porcine and bovine coronary arteries (0.04 ± 0.02 and 0.51 ± 0.08 ng/μg of total protein). A representative blot is shown in Fig. 4B. The subcellular distribution of ALDH2 is shown in Fig. 4C (summary data) and Fig. 4D (representative blot). Rat aorta contained 16.4 ± 1.73 and 2.0 ± 0.31 ng of ALDH2 per mg wet weight in cytosolic and mitochondrial fractions, respectively, confirming the predominant cytosolic localization of ALDH2 in rodent blood vessels observed previously [17,33]. Expression levels were considerably lower in the bovine vessels (3.0 ± 0.69 and 1.5 ± 0.25 ng/mg in cytosolic and mitochondrial fractions, respectively). In porcine coronary arteries ALDH2 was hardly detectable (<0.5 ng/mg). Note that pronounced differences in the recovery of cytosolic and mitochondrial protein (shown in the inset to Fig. 4C) may mislead judgment of band intensities in the blot (Fig. 4D), which was loaded with identical amounts of cytosolic and mitochondrial protein.
Affiliation: Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Austria.