Abstract 2297: Reduction in Myocardial Ischemia-reperfusion Injury in Group V Secretory Phospholipase A2-deficient Mice
Phospholipase A2 (PLA2) catalyzes hydrolysis of membrane phospholipid and liberates free fatty acid and lysophospholipids, precursors of various bioactive lipid mediators. Although several different types of PLA2 have been implicated in the pathogenesis of myocardial ischemia, it remains to be determined which subtype of PLA2 may be related to myocardial ischemia. Secretory PLA2 group V (sPLA2V) is expressed abundantly in the heart, but its role in ischemic heart disease is unknown. We generated mice that lack sPLA2V (sPLA2V −/−) and studied their response to myocardial ischemia-reperfusion (I/R).
Methods and Results: sPLA2V −/− mice had no obvious abnormality in major tissues, and there was no difference in heart size, heart rate and blood pressure between sPLA2V−/− mice and sPLA2V+/+ (wild-type; WT) mice. In vivo myocardial I/R was created in 10 –14 week-old male mice by 1-hr ligation of left anterior descending coronary artery, followed by 24 hrs of reperfusion. WT mice had an increased expression level of sPLA2V mRNA and protein in the ischemic myocardium by 3~5-fold of baseline. WT mice had a strong immunoreactivity of sPLA2V in ischemic myocardium in the immunohistochemical study. The sPLA2V −/− mice had a 34% decrease in myocardial infarct size and a preservation of echocardiographic LV function (%fractional shortening; 40% vs. 21%, respectively) after I/R, as compared with WT mice. The sPLA2V−/− mice had a 25% and 35% decrease in caspase-3 and caspase-8 activity, respectively, and a 33% decrease in TUNEL-positive apoptotic cells in the ischemic myocardium as compared with WT mice. The contents of thromboxane B2 and leukotriene B4, arachidonic acid-derived mediators, in the ischemic myocardium were 28% and 31% lower, respectively, in sPLA2V −/− mice than WT mice. The cultured cardiomyocytes from sPLA2V −/− mice had a 29% lower of arachidonic acid release after exposure to H2O2, as compared with WT mice.
Conclusions: Myocardial I/R injury is attenuated in sPLA2V−/− mice, as evidenced by a significant decrease in size of myocardial infarction with preservation of LV systolic function, a decrease in arachidonic acid-derived proinflammatory mediators and reduced apoptosis. Group V sPLA2 has an important role in the pathogenesis of myocardial I/R injury.