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

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Abstract
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. 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 κB (NFκB) in I/R tissue. Experiments using the NFκB inhibitor pyrrolidinedithiocarbamate also support that protection lent by OA-NO2 was in part mediated by inhibition of NFκB. OA-NO2 inhibition of NFκB activation was accompanied by suppression of downstream intercellular adhesion molecule 1 and monocyte chemotactic protein 1 expression, neutrophil infiltration, and myocyte apoptosis. 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.