Open AccessReduction in Myocardial Ischemia/Reperfusion Injury in Group X Secretory Phospholipase A 2 –Deficient Mice
Author(s) -
Daisuke Fujioka,
Yukio Saitō,
Tsuyoshi Kobayashi,
Toshiaki Yano,
Hiroyasu Tezuka,
Yoshikazu Ishimoto,
Noriko Suzuki,
Yusuke Yokota,
Takamitsu Nakamura,
Jyun-ei Obata,
Masato Kanazawa,
Ken−ichi Kawabata,
Kohji Hanasaki,
Kiyotaka Kugiyama
Publication year - 2008
Publication title -
circulation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.795
H-Index - 607
eISSN - 1524-4539
pISSN - 0009-7322
DOI - 10.1161/circulationaha.107.743997
Subject(s) - arachidonic acid , medicine , phospholipase a2 , ischemia , phospholipase , platelet , pharmacology , myeloperoxidase , phospholipase a , reperfusion injury , endocrinology , biochemistry , inflammation , enzyme , biology
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.