title: An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation.
abstract: The identity of the cellular mechanisms through which nitroglycerin (glyceryl trinitrate, GTN) elicits nitric oxide (NO)-based signaling to dilate blood vessels remains one of the longest standing foci of investigation and sources of controversy in cardiovascular biology. Recent evidence suggests an unexpected role for mitochondria. We show here that bioconversion by mitochondria of clinically relevant concentrations of GTN results in activation of guanylate cyclase, production of cGMP, vasodilation in vitro, and lowered blood pressure in vivo, which are eliminated by genetic deletion of the mitochondrial aldehyde dehydrogenase (mtALDH). In contrast, generation of vasoactivity from alternative nitro(so)-vasodilators is unaffected. In mtALDH(-/-) mice and their isolated vascular tissue, GTN bioactivity can still be generated, but only at substantially higher concentrations of GTN and by a mechanism that does not exhibit tolerance. Thus, mtALDH is necessary and sufficient for vasoactivity derived from therapeutic levels of GTN, and, more generally, mitochondria can serve as a source of NO-based cellular signals that may originate independently of NO synthase activity.
authors.affiliation: Department of Medicine and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Chen
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Foster
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Lan
authors.initials: L
authors.lastname: Mao
authors.forename: Howard A
authors.initials: HA
authors.lastname: Rockman
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kitagawa
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Hess
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Stamler
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D017353:Gene Deletion; D006162:Guanylate Cyclase / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D005996:Nitroglycerin / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction; D014664:Vasodilation / Q000187:drug effects
chemical_list: D009569:Nitric Oxide; D000444:Aldehyde Dehydrogenase; D006162:Guanylate Cyclase; D005996:Nitroglycerin; D006152:Cyclic GMP