(Circulation. 1996;94:1713-1718.)
© 1996 American Heart Association, Inc.
Articles |
Phospholipase D Plays a Role in Ischemic Preconditioning in Rabbit Heart
the Departments of Medicine and Physiology (M.V.C., Y.L., G.S.L., P.W., C.W., J.M.D.), University of South Alabama College of Medicine, Mobile, and the Department of Surgery (G.A.C., D.K.D.), University of Connecticut, School of Medicine, Farmington.
Correspondence to Michael V. Cohen, MD, MSB 3050, University of South Alabama, Mobile, AL 36688.
Background Activation of protein kinase C (PKC) is thought to be a critical step in ischemic preconditioning. Many receptor agonists activate PKC via stimulation of phospholipase C (PLC), which degrades membrane phospholipids to diacylglycerol (DAG), an important PKC cofactor. However, adenosine receptors, critical components of the prototypical preconditioning pathway, are not thought to couple to PLC in the cardiomyocyte. We therefore tested whether ischemic preconditioning or adenosine might instead activate phospholipase D (PLD) to produce DAG.
Methods and Results PLD activity was measured in isolated rabbit hearts. Ischemic injury was evaluated in either isolated rabbit hearts or dispersed myocytes. PLD activity doubled from a control level of 74.8±10.0 to 140.0±11.5 µmol·min-1·g-1 (P<.025) after two 5-minute periods of global ischemia separated by 5 minutes of reperfusion. A similar increase was noted after the heart had been exposed to (R)-N6-(2-phenylisopropyl)-adenosine [(R)-PIA] for 20 minutes. When sodium oleate, which activates PLD, was administered to isolated hearts before a 30-minute coronary occlusion, infarct size (15.6±2.0% of the risk zone) was significantly smaller than in untreated hearts (30.4±2.2%; P<.01). Exposure to sodium oleate significantly prolonged the rate of isolated myocyte survival during simulated ischemia. Propranolol 100 µmol/L, which blocks DAG production from metabolites produced by PLD catalysis, completely abolished the protective effects of both metabolic preconditioning and (R)-PIA exposure in myocytes.
Conclusions We conclude that PLD stimulation is involved in the protection of ischemic preconditioning in the rabbit heart.
Key Words: adenosine • receptors • enzymes • phospholipase D • myocardial infarction
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