An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Chen, Z; Foster, MW; Zhang, J; Mao, L; Rockman, HA; Kawamoto, T; Kitagawa, K; Nakayama, KI; Hess, DT; Stamler, JS

Published Date

  • August 23, 2005

Published In

Volume / Issue

  • 102 / 34

Start / End Page

  • 12159 - 12164

PubMed ID

  • 16103363

Pubmed Central ID

  • PMC1189320

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0503723102


  • eng

Conference Location

  • United States