Selective hydrolysis of plasmalogen phospholipids by Ca2+-independent PLA2 in hypoxic ventricular myocytes.
Accelerated phospholipid catabolism occurs early after the onset of myocardial ischemia and is likely to be mediated by the activation of one or more phospholipases in ischemic tissue. We hypothesized that hypoxia increases phospholipase A2 (PLA2) activity in isolated ventricular myocytes, resulting in increased lysophospholipid and arachidonic acid production, contributing to arrhythmogenesis in ischemic heart disease. The majority of ventricular myocyte arachidonic acid was found in plasmalogen phospholipids. Hypoxia increased membrane-associated, Ca2+-independent, plasmalogen-selective PLA2 activity, resulting in increased arachidonic acid release and lysoplasmenylcholine production. Pretreatment with the specific Ca2+-independent PLA2 inhibitor bromoenol lactone blocked hypoxia-induced increases in PLA2 activity, arachidonic acid release, and lysoplasmenylcholine production. Lysoplasmenylcholine produced action potential derangements, including shortening of action potential duration, and induced early and delayed afterdepolarizations in normoxic myocytes. The electrophysiological alterations induced by lysoplasmenylcholine would likely contribute to the initiation of arrhythmogenesis in the ischemic heart.
McHowat
J
J
Department of Pathology, St. Louis University Medical School, St. Louis, Missouri 63104, USA.
Liu
S
S
Creer
M H
MH
D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D015687:Cell Hypoxia; D002462:Cell Membrane / Q000201:enzymology; D005260:Female; D006352:Heart Ventricles / Q000201:enzymology; D006868:Hydrolysis; D007700:Kinetics; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology; D009206:Myocardium / Q000201:enzymology* / Q000648:ultrastructure; D009281:Naphthalenes / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D010743:Phospholipids / Q000032:analysis / Q000378:metabolism*; D010955:Plasmalogens / Q000378:metabolism*; D011753:Pyrones / Q000494:pharmacology; D011817:Rabbits
D008246:Lysophospholipids; D009281:Naphthalenes; D010726:Phosphodiesterase Inhibitors; D010743:Phospholipids; D010955:Plasmalogens; D011753:Pyrones; C021215:lysoplasmalogens; D016718:Arachidonic Acid; C068314:6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one; D000255:Adenosine Triphosphate; D010741:Phospholipases A; D054467:Phospholipases A2; D002118:Calcium