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Vascular bioactivation of nitroglycerin is catalyzed by cytosolic aldehyde dehydrogenase-2.
Circ Res. 2012 Feb 03; 110(3):385-93.CircR

Abstract

RATIONALE

According to general view, aldehyde dehydrogenase-2 (ALDH2) catalyzes the high-affinity pathway of vascular nitroglycerin (GTN) bioactivation in smooth muscle mitochondria. Despite having wide implications to GTN pharmacology and raising many questions that are still unresolved, mitochondrial bioactivation of GTN in blood vessels is still lacking experimental support.

OBJECTIVE

In the present study, we investigated whether bioactivation of GTN is affected by the subcellular localization of ALDH2 using immortalized ALDH2-deficient aortic smooth muscle cells and mouse aortas with selective overexpression of the enzyme in either cytosol or mitochondria.

METHODS AND RESULTS

Quantitative Western blotting revealed that ALDH2 is mainly cytosolic in mouse aorta and human coronary arteries, with only approximately 15% (mouse) and approximately 5% (human) of the enzyme being localized in mitochondria. Infection of ALDH2-deficient aortic smooth muscle cells or isolated aortas with adenovirus containing ALDH2 cDNA with or without the mitochondrial signal peptide sequence led to selective expression of the protein in mitochondria and cytosol, respectively. Cytosolic overexpression of ALDH2 restored GTN-induced relaxation and GTN denitration to wild-type levels, whereas overexpression in mitochondria (6-fold vs wild-type) had no effect on relaxation. Overexpression of ALDH2 in the cytosol of ALDH2-deficient aortic smooth muscle cells led to a significant increase in GTN denitration and cyclic GMP accumulation, whereas mitochondrial overexpression had no effect.

CONCLUSIONS

The data indicate that vascular bioactivation of GTN is catalyzed by cytosolic ALDH2. Mitochondrial GTN metabolism may contribute to oxidative stress-related adverse effects of nitrate therapy and the development of nitrate tolerance.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Karl-Franzens Universität Graz, Austria.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22207712

Citation

Beretta, Matteo, et al. "Vascular Bioactivation of Nitroglycerin Is Catalyzed By Cytosolic Aldehyde Dehydrogenase-2." Circulation Research, vol. 110, no. 3, 2012, pp. 385-93.
Beretta M, Wölkart G, Schernthaner M, et al. Vascular bioactivation of nitroglycerin is catalyzed by cytosolic aldehyde dehydrogenase-2. Circ Res. 2012;110(3):385-93.
Beretta, M., Wölkart, G., Schernthaner, M., Griesberger, M., Neubauer, R., Schmidt, K., Sacherer, M., Heinzel, F. R., Kohlwein, S. D., & Mayer, B. (2012). Vascular bioactivation of nitroglycerin is catalyzed by cytosolic aldehyde dehydrogenase-2. Circulation Research, 110(3), 385-93. https://doi.org/10.1161/CIRCRESAHA.111.245837
Beretta M, et al. Vascular Bioactivation of Nitroglycerin Is Catalyzed By Cytosolic Aldehyde Dehydrogenase-2. Circ Res. 2012 Feb 3;110(3):385-93. PubMed PMID: 22207712.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Vascular bioactivation of nitroglycerin is catalyzed by cytosolic aldehyde dehydrogenase-2. AU - Beretta,Matteo, AU - Wölkart,Gerald, AU - Schernthaner,Michaela, AU - Griesberger,Martina, AU - Neubauer,Regina, AU - Schmidt,Kurt, AU - Sacherer,Michael, AU - Heinzel,Frank R, AU - Kohlwein,Sepp D, AU - Mayer,Bernd, Y1 - 2011/12/29/ PY - 2011/12/31/entrez PY - 2011/12/31/pubmed PY - 2012/4/21/medline SP - 385 EP - 93 JF - Circulation research JO - Circ Res VL - 110 IS - 3 N2 - RATIONALE: According to general view, aldehyde dehydrogenase-2 (ALDH2) catalyzes the high-affinity pathway of vascular nitroglycerin (GTN) bioactivation in smooth muscle mitochondria. Despite having wide implications to GTN pharmacology and raising many questions that are still unresolved, mitochondrial bioactivation of GTN in blood vessels is still lacking experimental support. OBJECTIVE: In the present study, we investigated whether bioactivation of GTN is affected by the subcellular localization of ALDH2 using immortalized ALDH2-deficient aortic smooth muscle cells and mouse aortas with selective overexpression of the enzyme in either cytosol or mitochondria. METHODS AND RESULTS: Quantitative Western blotting revealed that ALDH2 is mainly cytosolic in mouse aorta and human coronary arteries, with only approximately 15% (mouse) and approximately 5% (human) of the enzyme being localized in mitochondria. Infection of ALDH2-deficient aortic smooth muscle cells or isolated aortas with adenovirus containing ALDH2 cDNA with or without the mitochondrial signal peptide sequence led to selective expression of the protein in mitochondria and cytosol, respectively. Cytosolic overexpression of ALDH2 restored GTN-induced relaxation and GTN denitration to wild-type levels, whereas overexpression in mitochondria (6-fold vs wild-type) had no effect on relaxation. Overexpression of ALDH2 in the cytosol of ALDH2-deficient aortic smooth muscle cells led to a significant increase in GTN denitration and cyclic GMP accumulation, whereas mitochondrial overexpression had no effect. CONCLUSIONS: The data indicate that vascular bioactivation of GTN is catalyzed by cytosolic ALDH2. Mitochondrial GTN metabolism may contribute to oxidative stress-related adverse effects of nitrate therapy and the development of nitrate tolerance. SN - 1524-4571 UR - https://www.unboundmedicine.com/medline/citation/22207712/Vascular_bioactivation_of_nitroglycerin_is_catalyzed_by_cytosolic_aldehyde_dehydrogenase_2_ DB - PRIME DP - Unbound Medicine ER -