Disruption of group IVA cytosolic phospholipase A2attenuates myocardial ischemia-reperfusion injury partly through inhibition of TNF-α-mediated pathway
Copyright policy )Disruption of group IVA cytosolic phospholipase A2attenuates myocardial ischemia-reperfusion injury partly through inhibition of TNF-α-mediated pathway
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.
- University of Tokyo Japan
- University of Yamanashi Japan
Male, Mice, Knockout, Tumor Necrosis Factor-alpha, Group IV Phospholipases A2, Myocardial Infarction, Myocardial Reperfusion Injury, Leukotriene B4, Receptors, Tumor Necrosis Factor, Etanercept, Mice, Inbred C57BL, Thromboxane B2, Mice, Ventricular Dysfunction, Left, Immunoglobulin G, Models, Animal, Animals, Myocytes, Cardiac, Cells, Cultured, Signal Transduction
Male, Mice, Knockout, Tumor Necrosis Factor-alpha, Group IV Phospholipases A2, Myocardial Infarction, Myocardial Reperfusion Injury, Leukotriene B4, Receptors, Tumor Necrosis Factor, Etanercept, Mice, Inbred C57BL, Thromboxane B2, Mice, Ventricular Dysfunction, Left, Immunoglobulin G, Models, Animal, Animals, Myocytes, Cardiac, Cells, Cultured, Signal Transduction
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