Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer

Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial... Nitrite (NO 2 − ) is an intrinsic signaling molecule that is reduced to NO during ischemia and limits apoptosis and cytotoxicity at reperfusion in the mammalian heart, liver, and brain. Although the mechanism of nitrite-mediated cytoprotection is unknown, NO is a mediator of the ischemic preconditioning cell-survival program. Analogous to the temporally distinct acute and delayed ischemic preconditioning cytoprotective phenotypes, we report that both acute and delayed (24 h before ischemia) exposure to physiological concentrations of nitrite, given both systemically or orally, potently limits cardiac and hepatic reperfusion injury. This cytoprotection is associated with increases in mitochondrial oxidative phosphorylation. Remarkably, isolated mitochondria subjected to 30 min of anoxia followed by reoxygenation were directly protected by nitrite administered both in vitro during anoxia or in vivo 24 h before mitochondrial isolation. Mechanistically, nitrite dose-dependently modifies and inhibits complex I by posttranslational S-nitrosation; this dampens electron transfer and effectively reduces reperfusion reactive oxygen species generation and ameliorates oxidative inactivation of complexes II–IV and aconitase, thus preventing mitochondrial permeability transition pore opening and cytochrome c release. These data suggest that nitrite dynamically modulates mitochondrial resilience to reperfusion injury and may represent an effector of the cell-survival program of ischemic preconditioning and the Mediterranean diet. Footnotes D.J. Lefer and M.T. Gladwin contributed equally to this work. Abbreviations used: ALT, alanine aminotransferase; iNOS, inducible NO synthase; I/R, ischemia/reperfusion; PTIO, 2-phenyl-tetramethylimidazoline-1-oxyl-3-oxide; ROS, reactive oxygen species; SNO, S-nitrosothiol. Submitted: 26 January 2007 Accepted: 2 July 2007 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Experimental Medicine Rockefeller University Press

Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer

Download PDF
14 pages

Loading next page...
 
/lp/rockefeller-university-press/nitrite-augments-tolerance-to-ischemia-reperfusion-injury-via-the-s2h11bJH13

References (68)

Publisher
Rockefeller University Press
Copyright
© 2007 Rockefeller University Press
ISSN
0022-1007
eISSN
1540-9538
DOI
10.1084/jem.20070198
pmid
17682069
Publisher site
See Article on Publisher Site

Abstract

Nitrite (NO 2 − ) is an intrinsic signaling molecule that is reduced to NO during ischemia and limits apoptosis and cytotoxicity at reperfusion in the mammalian heart, liver, and brain. Although the mechanism of nitrite-mediated cytoprotection is unknown, NO is a mediator of the ischemic preconditioning cell-survival program. Analogous to the temporally distinct acute and delayed ischemic preconditioning cytoprotective phenotypes, we report that both acute and delayed (24 h before ischemia) exposure to physiological concentrations of nitrite, given both systemically or orally, potently limits cardiac and hepatic reperfusion injury. This cytoprotection is associated with increases in mitochondrial oxidative phosphorylation. Remarkably, isolated mitochondria subjected to 30 min of anoxia followed by reoxygenation were directly protected by nitrite administered both in vitro during anoxia or in vivo 24 h before mitochondrial isolation. Mechanistically, nitrite dose-dependently modifies and inhibits complex I by posttranslational S-nitrosation; this dampens electron transfer and effectively reduces reperfusion reactive oxygen species generation and ameliorates oxidative inactivation of complexes II–IV and aconitase, thus preventing mitochondrial permeability transition pore opening and cytochrome c release. These data suggest that nitrite dynamically modulates mitochondrial resilience to reperfusion injury and may represent an effector of the cell-survival program of ischemic preconditioning and the Mediterranean diet. Footnotes D.J. Lefer and M.T. Gladwin contributed equally to this work. Abbreviations used: ALT, alanine aminotransferase; iNOS, inducible NO synthase; I/R, ischemia/reperfusion; PTIO, 2-phenyl-tetramethylimidazoline-1-oxyl-3-oxide; ROS, reactive oxygen species; SNO, S-nitrosothiol. Submitted: 26 January 2007 Accepted: 2 July 2007

Journal

The Journal of Experimental Medicine – Rockefeller University Press

Published: Sep 3, 2007

There are no references for this article.