An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation

Zhiqiang Chen, Matthew W. Foster, Jian Zhang, Lan Mao, Howard A. Rockman, Toshihiro Kawamoto, Kyoko Kitagawa, Keiichi Nakayama, Douglas T. Hess, Jonathan S. Stamler

研究成果: ジャーナルへの寄稿記事

173 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)12159-12164
ページ数6
ジャーナルProceedings of the National Academy of Sciences of the United States of America
102
発行部数34
DOI
出版物ステータス出版済み - 8 23 2005

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Nitroglycerin
Mitochondria
Blood Vessels
Nitric Oxide
Guanylate Cyclase
Vasodilator Agents
Vasodilation
Nitric Oxide Synthase
Mitochondrial Aldehyde Dehydrogenase
Blood Pressure

All Science Journal Classification (ASJC) codes

  • General

これを引用

An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation. / Chen, Zhiqiang; Foster, Matthew W.; Zhang, Jian; Mao, Lan; Rockman, Howard A.; Kawamoto, Toshihiro; Kitagawa, Kyoko; Nakayama, Keiichi; Hess, Douglas T.; Stamler, Jonathan S.

:: Proceedings of the National Academy of Sciences of the United States of America, 巻 102, 番号 34, 23.08.2005, p. 12159-12164.

研究成果: ジャーナルへの寄稿記事

Chen, Z, Foster, MW, Zhang, J, Mao, L, Rockman, HA, Kawamoto, T, Kitagawa, K, Nakayama, K, Hess, DT & Stamler, JS 2005, 'An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation', Proceedings of the National Academy of Sciences of the United States of America, 巻. 102, 番号 34, pp. 12159-12164. https://doi.org/10.1073/pnas.0503723102
Chen, Zhiqiang ; Foster, Matthew W. ; Zhang, Jian ; Mao, Lan ; Rockman, Howard A. ; Kawamoto, Toshihiro ; Kitagawa, Kyoko ; Nakayama, Keiichi ; Hess, Douglas T. ; Stamler, Jonathan S. / An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation. :: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; 巻 102, 番号 34. pp. 12159-12164.
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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.",
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