Published Online
on May 27, 2008

A more recent version of this article appeared on June 10, 2008

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Submitted on October 4, 2007
Accepted on April 11, 2008

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

Daisuke Fujioka MD, PhD, Yukio Saito MD, Tsuyoshi Kobayashi MD, Toshiaki Yano MD, Hideo Tezuka MD, PhD, Yoshikazu Ishimoto PhD, Noriko Suzuki PhD, Yasunori Yokota PhD, Takamitsu Nakamura MD, Jyun-ei Obata MD, PhD, Masaki Kanazawa MD, Ken-ichi Kawabata MD, PhD, Kohji Hanasaki PhD, and Kiyotaka Kugiyama MD, PhD^*

From the Department of Internal Medicine II (D.F., Y.S., T.K., T.Y., T.N., J.O., M.K., K. Kawabata, K. Kugiyama), and Laboratory Animal Support Section (H.T.), Center for Life Science Research, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi; and Shionogi Research Laboratories, Shionogi and Co Ltd, Osaka (Y.I., N.S., Y.Y., K.H.), Japan.

^* To whom correspondence should be addressed. E-mail: kugiyama{at}yamanashi.ac.jp.

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.

Key words: myocardial infarction • polymorphonuclear leukocytes • secretory phospholipase A₂

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