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

Circulation. 2008 Jun 10;117(23):2977-85. doi: 10.1161/CIRCULATIONAHA.107.743997. Epub 2008 May 27.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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