Cardiac ischemia activates calcium-independent phospholipase A2β, precipitating ventricular tachyarrhythmias in transgenic mice: Rescue of the lethal electrophysiologic phenotype by mechanism-based inhibition

David J. Mancuso, Dana R. Abendschein, Christopher M. Jenkins, Xianlin Han, Jeffrey E. Saffitz, Richard B. Schuessler, Richard W. Gross

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

Murine myocardium contains diminutive amounts of calcium-independent phospholipase A2 (iPLA2) activity (<5% that of human heart), and malignant ventricular tachyarrhythmias are infrequent during acute murine myocardial ischemia. Accordingly we considered the possibility that the mouse was a species-specific knockdown of the human pathologic phenotype of ischemia-induced lethal ventricular tachyarrhythmias. Transgenic mice were generated expressing amounts of iPLA2β activity comparable to that present in human myocardium. Coronary artery occlusion in Langendorff perfused hearts from transgenic mice resulted in a 22-fold increase in fatty acids released into the venous eluent (29.4 nmol/ml in transgenic versus 1.35 nmol/ml of eluent in wild-type mice), a 4-fold increase in lysophosphatidylcholine mass in ischemic zones (4.9 nmol/mg in transgenic versus 1.1 nmol/mg of protein in wild-type mice), and malignant ventricular tachyarrhythmias within minutes of ischemia. Neither normally perfused transgenic nor ischemic wild-type hearts demonstrated these alterations. Pretreatment of Langendorff perfused transgenic hearts with the iPLA2 mechanism-based inhibitor (E)-6-(bromomethylene)-3-(1-naphthalenyl)-2Htetrahydropyran-2-one (BEL) just minutes prior to induction of ischemia completely ablated fatty acid release and lysolipid accumulation and rescued transgenic hearts from malignant ventricular tachyarrhythmias. Collectively these results demonstrate that ischemia activates iPLA2β in intact myocardium and that iPLA2β-mediated hydrolysis of membrane phospholipids can induce lethal malignant ventricular tachyarrhythmias during acute cardiac ischemia.

Original languageEnglish (US)
Pages (from-to)22231-22236
Number of pages6
JournalJournal of Biological Chemistry
Volume278
Issue number25
DOIs
StatePublished - Jun 20 2003
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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