title: ALDH-2 deficiency increases cardiovascular oxidative stress--evidence for indirect antioxidative properties.
abstract: Mitochondrial aldehyde dehydrogenase (ALDH-2) reduces reactive oxygen species (ROS) formation related to toxic aldehydes; additionally, it provides a bioactivating pathway for nitroglycerin. Since acetaldehyde, nitroglycerin, and doxorubicin treatment provoke mitochondrial oxidative stress, we used ALDH-2(-/-) mice and purified recombinant human ALDH-2 to test the hypothesis that ALDH-2 has an indirect antioxidant function in mitochondria. Antioxidant capacity of purified ALDH-2 was comparable to equimolar doses of glutathione, cysteine, and dithiothreitol; mitochondrial oxidative stress was comparable in C57Bl6 and ALDH-2(-/-) mice after acute challenges with nitroglycerin or doxorubicin, whereas chronic acetaldehyde, nitroglycerin, and doxorubicin treatment dose-dependently increased mitochondrial ROS formation and impaired endothelial function to a greater extent in ALDH-2(-/-) mice. Maximal nitroglycerin dose applied in vivo lead to a "super-desensitized" nitroglycerin response in isolated ALDH-2(-/-) aortas, inaccessible in C57Bl6 mice. Our results suggest that ALDH-2 has an indirect antioxidative property independent of its thiol-moiety in disease states of cardiovascular oxidative stress.
authors.affiliation: II. Medizinische Klinik, Labor für Molekulare Kardiologie, Johannes-Gutenberg-Universität Mainz, Langenbeck Str. 1, 55131 Mainz, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Wenzel
authors.forename: Johanna
authors.initials: J
authors.lastname: Müller
authors.forename: Sarah
authors.initials: S
authors.lastname: Zurmeyer
authors.forename: Swenja
authors.initials: S
authors.lastname: Schuhmacher
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schulz
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.forename: Andrea
authors.initials: A
authors.lastname: Pautz
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Leszek
authors.initials: L
authors.lastname: Wojnowski
authors.forename: Hartmut
authors.initials: H
authors.lastname: Kleinert
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
mesh_terms: D000079:Acetaldehyde / Q000494:pharmacology; D000444:Aldehyde Dehydrogenase / Q000172:deficiency* / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003545:Cysteine / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000201:enzymology*; D008954:Models, Biological; D005996:Nitroglycerin / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D004317:Doxorubicin; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D005996:Nitroglycerin; D005978:Glutathione; D000079:Acetaldehyde; D003545:Cysteine; D004229:Dithiothreitol