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Cardiovascular Research Advance Access first published online on August 7, 2009
This version [Corrected Proof] published online on September 2, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp275
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Endogenous generation and protective effects of nitro-fatty acids in a murine model of focal cardiac ischaemia and reperfusion

Volker Rudolph1,2,*,{dagger}, Tanja K. Rudolph1,2,{dagger}, Francisco J. Schopfer1, Gustavo Bonacci1, Steven R. Woodcock1, Marsha P. Cole1, Paul R.S. Baker1, Ravi Ramani3 and Bruce A. Freeman1,*

1 Department of Pharmacology and Chemical Biology, University of Pittsburgh, E1340 Thomas E. Starzl Biomedical Science Tower, 200 Lothrop St, Pittsburgh, PA 15261, USA
2 Cardiovascular Research Center, University Heart Center Hamburg, Hamburg, Germany
3 Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA, USA

* Corresponding author. Tel: +1 412 648 9319, Fax: +1 412 648 2229, Email: vrudolph{at}pitt.edu (V.R.)/freerad{at}pitt.edu (B.A.F.)

Aims: Nitrated fatty acids (NO2-FA) have been identified as endogenous anti-inflammatory signalling mediators generated by oxidative inflammatory reactions. Herein the in vivo generation of nitro-oleic acid (OA-NO2) and nitro-linoleic acid (LNO2) was measured in a murine model of myocardial ischaemia and reperfusion (I/R) and the effect of exogenous administration of OA-NO2 on I/R injury was evaluated.

Methods and results: In C57/BL6 mice subjected to 30 min of coronary artery ligation, endogenous OA-NO2 and LNO2 formation was observed after 30 min of reperfusion, whereas no NO2-FA were detected in sham-operated mice and mice with myocardial infarction without reperfusion. Exogenous administration of 20 nmol/g body weight OA-NO2 during the ischaemic episode induced profound protection against I/R injury with a 46% reduction in infarct size (normalized to area at risk) and a marked preservation of left ventricular function as assessed by transthoracic echocardiography, compared with vehicle-treated mice. Administration of OA-NO2 inhibited activation of the p65 subunit of nuclear factor {kappa}B (NF{kappa}B) in I/R tissue. Experiments using the NF{kappa}B inhibitor pyrrolidinedithiocarbamate also support that protection lent by OA-NO2 was in part mediated by inhibition of NF{kappa}B. OA-NO2 inhibition of NF{kappa}B activation was accompanied by suppression of downstream intercellular adhesion molecule 1 and monocyte chemotactic protein 1 expression, neutrophil infiltration, and myocyte apoptosis.

Conclusion: This study reveals the de novo generation of fatty acid nitration products in vivo and reveals the anti-inflammatory and potential therapeutic actions of OA-NO2 in myocardial I/R injury.

KEYWORDS Ischaemia/reperfusion; Nitric oxide; Nitro-fatty acids; Reactive oxygen species; Oxides of nitrogen; Lipid signalling

Time for primary review: 21 days

{dagger} The first two authors contributed equally to the study.


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