This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 117/23/2977    most recent CIRCULATIONAHA.107.743997v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Fujioka, D. Articles by Kugiyama, K. Search for Related Content PubMed PubMed Citation Articles by Fujioka, D. Articles by Kugiyama, K. Related Collections Genetically altered mice Ischemic biology - basic studies Related Article

(Circulation. 2008;117:2977-2985.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

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; 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.

Correspondence to Kiyotaka Kugiyama, MD, PhD, Department of Internal Medicine II, University of Yamanashi, Faculty of Medicine, 1110 Shimokato, Chuo City, Yamanashi, 409-3898 Japan. E-mail kugiyama{at}yamanashi.ac.jp

Received October 4, 2007; accepted April 11, 2008.

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.

---

 

CLINICAL PERSPECTIVE

Related Article:

Clinical Summaries
Circulation 2008 117: 2961-2962. [Extract] [Full Text]