Abstract 15081: Group V Secretory Phospholipase A2 Plays a Role in Myocardial Ischemia Reperfusion Injury Through Cytosolic Phospholipase A2.
Phospholipase A2 (PLA2) catalyzes hydrolysis of membrane phospholipid and liberates free fatty acid and lysophospholipids. Among various PLA2, group V secretory PLA2 (sPLA2-V) and group IV cytosolic PLA2 (cPLA2) are highly expressed in the hearts, and they are implicated in the pathogenesis of myocardial ischemia. In previous reports, exogenous addition of sPLA2-V works in concert with cPLA2 to produce eiocsanoids in the inflammatory cells, indicating a cross-talk between sPLA2-V and cPLA2 in a certain condition. This study examined (1) role of endogenous sPLA2-V in myocardial ischemia-reperfusion (I/R) injury, (2) cooperated action of sPLA2-V and cPLA2 in myocardial I/R injury using sPLA2-V knockout (sPLA2-V −/−) mice.
Methods and Results: 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. The sPLA2-V −/− 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 wild type (WT) mice. The contents of leukotriene B4 (LTB4) and thromboxane B2 (TXB2), arachidonic acid-derived mediators, in the ischemic myocardium were 28% and 31% lower, respectively, in sPLA2-V −/− mice than WT mice. Intraperitoneal administration of AACOCF3 or MAFP, inhibitors of cPLA2 activity, decreased myocardial infarct size and myocardial content of LTB4 and TXB2 in both genotyped mice. The decrease in myocardial infarct size and content of LTB4 and TXB2 after cPLA2 inhibitor was greater in WT mice than sPLA2-V −/− mice, resulting in no significant difference in these parameters after cPLA2 inhibitor between sPLA2-V −/− mice and WT mice. I/R increased phosphorylation of ERK, JNK and p38 MAP kinases in ischemic myocardium in association with the subsequent phosphorylation of cPLA2. The increase in phosphorylation of p38 and cPLA2 but not ERK and JNK was less in sPLA2-V −/− mice than the WT mice. Pretreatment with p38 inhibitor suppressed an increase in cPLA2 phosphorylation after I/R in the WT mice but not sPLA2-V −/− mice.
Conclusions: Group V sPLA2 has a pathogenetic role in myocardial I/R injury partly through the sequential activation of p38 and cPLA2.
- © 2010 by American Heart Association, Inc.