Cardiac ischemia activates calcium-independent phospholipase A2beta, precipitating ventricular tachyarrhythmias in transgenic mice: rescue of the lethal electrophysiologic phenotype by mechanism-based inhibition.
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 ischemiainduced lethal ventricular tachyarrhythmias. Transgenic mice were generated expressing amounts of iPLA2beta 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)-2H-tetrahydropyran-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 iPLA2beta in intact myocardium and that iPLA2beta-mediated hydrolysis of membrane phospholipids can induce lethal malignant ventricular tachyarrhythmias during acute cardiac ischemia.
Division of Bioorganic Chemistry and Molecular Pharmacology. Washington University School of Medicine, St. Louis, Missouri 63110, USA.
David J
DJ
Mancuso
Dana R
DR
Abendschein
Christopher M
CM
Jenkins
Xianlin
X
Han
Jeffrey E
JE
Saffitz
Richard B
RB
Schuessler
Richard W
RW
Gross
D000818:Animals; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation; D054513:Group IV Phospholipases A2; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000201:enzymology*; D010641:Phenotype; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D021241:Spectrometry, Mass, Electrospray Ionization; D017180:Tachycardia, Ventricular / Q000209:etiology*
D010741:Phospholipases A; D054513:Group IV Phospholipases A2; D054467:Phospholipases A2