Vascular Bioactivation of Nitroglycerin Is Catalyzed by Cytosolic Aldehyde Dehydrogenase-2.

Circ Res. 2011 Dec 29;
Beretta M, Wlkart G, Schernthaner M, Griesberger M, Neubauer R, Schmidt K, Sacherer M, Heinzel FR, Kohlwein SD, Mayer B

Rationale:According to ubiquitous view, aldehyde dehydrogenase-2 (ALDH2) catalyzes a high-affinity pathway of vascular nitroglycerin (GTN) bioactivation in well-spoken muscle mitochondria. Despite carrying wide implications to GTN pharmacology as well as raising many questions which are still unresolved, mitochondrial bioactivation of GTN in red blood vessels is still not in experimental support.Objective:In a present study, you investigated whether bioactivation of GTN is affected by a subcellular localization of ALDH2 regulating immortalized ALDH2-deficient aortic well-spoken muscle cells as well as rodent aortas with selective overexpression of a enzyme in either cytosol or mitochondria.Methods as well as Results:Quantitative Western blotting revealed which ALDH2 is mainly cytosolic in rodent aorta as well as human coronary arteries, with only approximately 15% (mouse) as well as approximately 5% (human) of a enzyme being localized in mitochondria. Infection of ALDH2-deficient aortic well-spoken muscle cells or removed aortas with adenovirus containing ALDH2 cDNA with or but a mitochondrial signal peptide method led to selective expression of a protein in mitochondria as well as cytosol, respectively. Cytosolic overexpression of ALDH2 restored GTN-induced decrease as well as GTN denitration to wild-type levels, whereas overexpression in mitochondria (6-fold vs wild-type) had no outcome on relaxation. Overexpression of ALDH2 in a cytosol of ALDH2-deficient aortic well-spoken muscle cells led to a significant increase in GTN denitration as well as cyclic GMP accumulation, whereas mitochondrial overexpression had no effect.Conclusions:The data indicate which vascular bioactivation of GTN is catalyzed by cytosolic ALDH2. Mitochondrial GTN metabolism may contribute to oxidative stress-related adverse goods of nitrate therapy as well as a development of nitrate tolerance.

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