Reduction in myocardial ischemia/reperfusion injury in group X secretory phospholipase A2-deficient mice.

Abstract

BACKGROUND:

Group X secretory phospholipase A(2) (sPLA(2)-X) has the most potent hydrolyzing activity toward phosphatidylcholine and elicits a marked release of arachidonic acid among several types of sPLA(2). sPLA(2)-X is expressed in neutrophils, but its pathogenic role remains unclear.

METHODS AND RESULTS:

We generated mice that lack sPLA(2)-X and studied their response to myocardial ischemia/reperfusion. The sPLA(2)-X(-/-) mice had a significant reduction in myocardial infarct size and a decrease in myocardial myeloperoxidase activity compared with sPLA(2)-X(+/+) mice. Myocardial infarct size was also significantly reduced in lethally irradiated sPLA(2)-X(+/+) mice reconstituted with sPLA(2)-X(-/-) bone marrow compared with sPLA(2)-X(+/+) bone marrow. The extent of myocardial ischemia/reperfusion injury was comparable between sPLA(2)-X(-/-) and sPLA(2)-X(+/+) mice in Langendorff experiments using isolated hearts and blood-free perfusion buffer, supporting a potential role of sPLA(2)-X in blood in myocardial ischemia/reperfusion injury. In the infarcted myocardium of sPLA(2)-X(+/+) mice, sPLA(2)-X was released from neutrophils but not myocardial tissues and platelets and was undetectable in the peripheral serum. The sPLA(2)-X(-/-) mice had lower accumulation of neutrophils in ischemic myocardium, and the isolated sPLA(2)-X(-/-) neutrophils had lower release of arachidonic acid and attenuated cytotoxic activities including respiratory burst compared with sPLA(2)-X(+/+) neutrophils. The attenuated functions of sPLA(2)-X(-/-) neutrophils were reversible by the exogenous addition of sPLA(2)-X protein. Furthermore, administration of a sPLA(2) inhibitor reduced myocardial infarct size and suppressed the cytotoxic activity of sPLA(2)-X(+/+) neutrophils.

CONCLUSIONS:

Myocardial ischemia/reperfusion injury was attenuated in sPLA(2)-X(-/-) mice partly through the suppression of neutrophil cytotoxic activities.

• Authors: Daisuke Fujioka, Yukio Saito, Tsuyoshi Kobayashi, Toshiaki Yano, Hideo Tezuka, Yoshikazu Ishimoto, Noriko Suzuki, Yasunori Yokota, Takamitsu Nakamura, Jyun-ei Obata, Masaki Kanazawa, Ken-ichi Kawabata, Kohji Hanasaki, Kiyotaka Kugiyama
• Journal: Circulation (Circulation) Vol. 117 Issue 23 Pg. 2977-85 (Jun 10 2008) ISSN: 1524-4539 [Electronic] United States
• PMID: 18506007 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetates
• Enzyme Inhibitors
• Indoles
• LY 329722
• Prodrugs
• Reactive Oxygen Species
• Arachidonic Acid
• Peroxidase
• Group X Phospholipases A2
• Pla2g10 protein, mouse

Topics

• Acetates
• Animals
• Arachidonic Acid (metabolism)
• Cells, Cultured
• Chemotaxis, Leukocyte (physiology)
• Echocardiography
• Enzyme Inhibitors (pharmacology)
• Group X Phospholipases A2 (antagonists & inhibitors, blood, genetics)
• Indoles
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Myocardial Infarction (diagnostic imaging, immunology, metabolism)
• Myocardial Reperfusion Injury (diagnostic imaging, immunology, metabolism)
• Myocytes, Cardiac (cytology, metabolism)
• Neutrophils (cytology, enzymology)
• Peroxidase (metabolism)
• Prodrugs (pharmacology)
• Reactive Oxygen Species (metabolism)