JPET Celsis microsomes equal better data

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 25, 2008; DOI: 10.1124/jpet.108.144352
This Article
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Google Scholar
Right arrow Articles by Jiao, X.
Right arrow Articles by Tao, L.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jiao, X.
Right arrow Articles by Tao, L.


Received for publication August 4, 2008.
Revised November 21, 2008.
Accepted for publication November 21, 2008.

INO-4885, a Peroxynitrite Decomposition Catalyst, Protects the Heart against Reperfusion Injury in Mice

Xiangying Jiao 1, Erhe Gao 1, Yuexing Yuang 1, Yajing Wang 1, Wayne Lau 1, Walter Koch 1, Xinliang Ma 1, Ling Tao 1*

1 Thomas Jefferson University

* Address correspondence to: E-mail: ling.tao{at}jefferson.edu

Abstract

Oxidative/nitrative stress caused by peroxynitrite (ONOO-), the reaction product of superoxide (O2-) and nitric oxide (NO), is the primary cause of myocardial ischemia/reperfusion injury. The present study determined if INO-4885, a new peroxynitrite decomposition catalyst, may provide cellular protection and protect heart from myocardial ischemia/reperfusion (MI/R) injury. Adult male mice were subjected to 30 min ischemia and 3 or 24 h of reperfusion. Mice were randomized to receive vehicle, INO-C (INO-4885 without catalytic moiety), or INO-4885 (3-300 µg/kg, intraperitoneally) 10 min before reperfusion. Infarct size, apoptosis, nitrotyrosine content, NO/O2- production and iNOS/NADPH oxidase expression were determined. INO-4885 treatment reduced ischemia/reperfusion-induced protein nitration and caspase 3 activation in a dose dependent fashion in the range of 3 to 100 µg/kg. However, doses exceeding 100 µg/kg produced nonspecific effects and attenuated its protective ability. At the optimal dose (30 µg/kg), INO-4885 significantly reduced infarct size (P<0.01), decreased apoptosis (P<0.01) and reduced tissue nitrotyrosine content (P<0.01). As expected, INO-4885 had no effect on ischemia/reperfusion-induced iNOS expression and NO overproduction. To our surprise, this compound significantly reduced superoxide production and partially blocked NADPH oxidase overexpression in the ischemic/reperfused cardiac tissue. Additional experiments demonstrated that INO-4885 provided better cardioprotection than 1400W (a selective iNOS inhibitor), apocynin (an NADPH oxidase inhibitor), or Tiron (a cell permeable superoxide scavenger). Taken together, our data demonstrated that INO-4885 is a cardioprotective molecule that attenuates myocardial reperfusion injury by facilitating peroxynitrite decomposition, as well as inhibiting NADPH oxidase-derived O2- production.


Key words: Antioxidant, Heart, Nitric Oxide, Peroxynitrite, Reperfusion injury, Superoxide




Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2008 by the American Society for Pharmacology and Experimental Therapeutics.