Disruption of group IVA cytosolic phospholipase A2attenuates myocardial ischemia-reperfusion injury partly through inhibition of TNF-α-mediated pathway

Abstract

Group IVA cytosolic phospholipase A2(cPLA2α), which preferentially cleaves arachidonic acid from phospholipids, plays a role in apoptosis and tissue injury. Downstream signals in response to tumor necrosis factor (TNF)-α, a mediator of myocardial ischemia-reperfusion (I/R) injury, involve cPLA2α activation. This study examined the potential role of cPLA2α and its mechanistic link with TNF-α in myocardial I/R injury using cPLA2α knockout (cPLA2α−/−) mice. Myocardial I/R was created with 10-wk-old male mice by 1 h ligation of the left anterior descending coronary artery, followed by 24 h of reperfusion. As a result, compared with wild-type (cPLA2α+/+) mice, cPLA2α−/−mice had a 47% decrease in myocardial infarct size, preservation of echocardiographic left ventricle (LV) function (%fractional shortening: 14 vs. 21%, respectively), and lower content of leukotriene B4and thromboxane B2(62 and 50% lower, respectively) in the ischemic myocardium after I/R. Treatment with the TNF-α inhibitor (soluble TNF receptor II/IgG1 Fc fusion protein, sTNFR:Fc) decreased myocardial I/R injury and LV dysfunction in cPLA2α+/+mice but not cPLA2α−/−mice. sTNFR:Fc also suppressed cPLA2α phosphorylation in the ischemic myocardium after I/R of cPLA2α+/+mice. Similarly, sTNFR:Fc exerted protective effects against hypoxia-reoxygenation (H/R)-induced injury in the cultured cardiomyocytes from cPLA2α+/+mice but not cPLA2α−/−cardiomyocytes. H/R and TNF-α induced cPLA2α phosphorylation in cPLA2α+/+cardiomyocytes, which was reversible by sTNFR:Fc. In cPLA2α−/−cardiomyocytes, TNF-α induced apoptosis and release of arachidonic acid to a lesser extent than in cPLA2α+/+cardiomyocytes. In conclusion, disruption of cPLA2α attenuates myocardial I/R injury partly through inhibition of TNF-α-mediated pathways.