Reduction in Myocardial Ischemia/Reperfusion Injury in Group X Secretory Phospholipase A2–Deficient Mice

D Fujioka, Y Saito, T Kobayashi, T Yano, H Tezuka… - Circulation, 2008 - Am Heart Assoc
D Fujioka, Y Saito, T Kobayashi, T Yano, H Tezuka, Y Ishimoto, N Suzuki, Y Yokota…
Circulation, 2008Am Heart Assoc
Background—Group X secretory phospholipase A2 (sPLA2-X) has the most potent
hydrolyzing activity toward phosphatidylcholine and elicits a marked release of arachidonic
acid among several types of sPLA2. sPLA2-X is expressed in neutrophils, but its pathogenic
role remains unclear. Methods and Results—We generated mice that lack sPLA2-X and
studied their response to myocardial ischemia/reperfusion. The sPLA2-X−/− mice had a
significant reduction in myocardial infarct size and a decrease in myocardial …
Background— Group X secretory phospholipase A2 (sPLA2-X) has the most potent hydrolyzing activity toward phosphatidylcholine and elicits a marked release of arachidonic acid among several types of sPLA2. sPLA2-X is expressed in neutrophils, but its pathogenic role remains unclear.
Methods and Results— We generated mice that lack sPLA2-X and studied their response to myocardial ischemia/reperfusion. The sPLA2-X−/− mice had a significant reduction in myocardial infarct size and a decrease in myocardial myeloperoxidase activity compared with sPLA2-X+/+ mice. Myocardial infarct size was also significantly reduced in lethally irradiated sPLA2-X+/+ mice reconstituted with sPLA2-X−/− bone marrow compared with sPLA2-X+/+ bone marrow. The extent of myocardial ischemia/reperfusion injury was comparable between sPLA2-X−/− and sPLA2-X+/+ mice in Langendorff experiments using isolated hearts and blood-free perfusion buffer, supporting a potential role of sPLA2-X in blood in myocardial ischemia/reperfusion injury. In the infarcted myocardium of sPLA2-X+/+ mice, sPLA2-X was released from neutrophils but not myocardial tissues and platelets and was undetectable in the peripheral serum. The sPLA2-X−/− mice had lower accumulation of neutrophils in ischemic myocardium, and the isolated sPLA2-X−/− neutrophils had lower release of arachidonic acid and attenuated cytotoxic activities including respiratory burst compared with sPLA2-X+/+ neutrophils. The attenuated functions of sPLA2-X−/− neutrophils were reversible by the exogenous addition of sPLA2-X protein. Furthermore, administration of a sPLA2 inhibitor reduced myocardial infarct size and suppressed the cytotoxic activity of sPLA2-X+/+ neutrophils.
Conclusions— Myocardial ischemia/reperfusion injury was attenuated in sPLA2-X−/− mice partly through the suppression of neutrophil cytotoxic activities.
Am Heart Assoc