HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 278, Issue 25, 22231-22236, June 20, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/25/22231    most recent C300033200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mancuso, D. J. Articles by Gross, R. W. Search for Related Content PubMed PubMed Citation Articles by Mancuso, D. J. Articles by Gross, R. W. Social Bookmarking                      What's this?

Cardiac Ischemia Activates Calcium-independent Phospholipase A₂, 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 || and Richard W. Gross   **  

From the Division of Bioorganic Chemistry and Molecular Pharmacology and the Departments of Medicine, ^**Chemistry, Molecular Biology and Pharmacology, ^||Surgery, and ^¶Pathology, Washington University School of Medicine, St. Louis, Missouri 63110

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 iPLA₂ 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 iPLA₂ in intact myocardium and that iPLA₂-mediated hydrolysis of membrane phospholipids can induce lethal malignant ventricular tachyarrhythmias during acute cardiac ischemia.

Received for publication, January 23, 2003 , and in revised form, March 20, 2003.

^* This research was supported jointly by National Institutes of Health Grants 2PO1HL57278-06A1 and 2RO1HL41250-10. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Division of Bioorganic Chemistry and Molecular Pharmacology, Dept. of Medicine, Washington University School of Medicine, 660 South Euclid Ave., Campus Box 8020, St. Louis, MO 63110. Tel.: 314-362-2690; Fax: 314-362-1402.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				D. Cohen, J. Papillon, L. Aoudjit, H. Li, A. V. Cybulsky, and T. Takano Role of calcium-independent phospholipase A2 in complement-mediated glomerular epithelial cell injury Am J Physiol Renal Physiol, March 1, 2008; 294(3): F469 - F479. [Abstract] [Full Text] [PDF]

				T. S. Hallstrand, E. Y. Chi, A. G. Singer, M. H. Gelb, and W. R. Henderson Jr. Secreted Phospholipase A2 Group X Overexpression in Asthma and Bronchial Hyperresponsiveness Am. J. Respir. Crit. Care Med., December 1, 2007; 176(11): 1072 - 1078. [Abstract] [Full Text] [PDF]

				K. A. Poulsen, S. F. Pedersen, M. Kolko, and I. H. Lambert Induction of group VIA phospholipase A2 activity during in vitro ischemia in C2C12 myotubes is associated with changes in the level of its splice variants Am J Physiol Cell Physiol, November 1, 2007; 293(5): C1605 - C1615. [Abstract] [Full Text] [PDF]

				K. J. Fogle, A. K. Lyashchenko, H. K. Turbendian, and G. R. Tibbs HCN Pacemaker Channel Activation Is Controlled by Acidic Lipids Downstream of Diacylglycerol Kinase and Phospholipase A2 J. Neurosci., March 14, 2007; 27(11): 2802 - 2814. [Abstract] [Full Text] [PDF]

				S. P. Levick, D. C. Loch, S. M. Taylor, and J. S. Janicki Arachidonic Acid Metabolism as a Potential Mediator of Cardiac Fibrosis Associated with Inflammation J. Immunol., January 15, 2007; 178(2): 641 - 646. [Abstract] [Full Text] [PDF]

				M. Ohtsuki, Y. Taketomi, S. Arata, S. Masuda, Y. Ishikawa, T. Ishii, Y. Takanezawa, J. Aoki, H. Arai, K. Yamamoto, et al. Transgenic Expression of Group V, but Not Group X, Secreted Phospholipase A2 in Mice Leads to Neonatal Lethality because of Lung Dysfunction J. Biol. Chem., November 24, 2006; 281(47): 36420 - 36433. [Abstract] [Full Text] [PDF]

				K. Seleznev, C. Zhao, X. H. Zhang, K. Song, and Z. A. Ma Calcium-independent Phospholipase A2 Localizes in and Protects Mitochondria during Apoptotic Induction by Staurosporine J. Biol. Chem., August 4, 2006; 281(31): 22275 - 22288. [Abstract] [Full Text] [PDF]

				S. Bao, H. Song, M. Wohltmann, S. Ramanadham, W. Jin, A. Bohrer, and J. Turk Insulin Secretory Responses and Phospholipid Composition of Pancreatic Islets from Mice That Do Not Express Group VIA Phospholipase A2 and Effects of Metabolic Stress on Glucose Homeostasis J. Biol. Chem., July 28, 2006; 281(30): 20958 - 20973. [Abstract] [Full Text] [PDF]

				C. M. Jenkins, W. Yan, D. J. Mancuso, and R. W. Gross Highly Selective Hydrolysis of Fatty Acyl-CoAs by Calcium-independent Phospholipase A2beta: ENZYME AUTOACYLATION AND ACYL-CoA-MEDIATED REVERSAL OF CALMODULIN INHIBITION OF PHOSPHOLIPASE A2 ACTIVITY J. Biol. Chem., June 9, 2006; 281(23): 15615 - 15624. [Abstract] [Full Text] [PDF]

				S. Bao, A. Bohrer, S. Ramanadham, W. Jin, S. Zhang, and J. Turk Effects of Stable Suppression of Group VIA Phospholipase A2 Expression on Phospholipid Content and Composition, Insulin Secretion, and Proliferation of INS-1 Insulinoma Cells J. Biol. Chem., January 6, 2006; 281(1): 187 - 198. [Abstract] [Full Text] [PDF]

				M. Murakami, S. Masuda, K. Ueda-Semmyo, E. Yoda, H. Kuwata, Y. Takanezawa, J. Aoki, H. Arai, H. Sumimoto, Y. Ishikawa, et al. Group VIB Ca2+-independent Phospholipase A2{gamma} Promotes Cellular Membrane Hydrolysis and Prostaglandin Production in a Manner Distinct from Other Intracellular Phospholipases A2 J. Biol. Chem., April 8, 2005; 280(14): 14028 - 14041. [Abstract] [Full Text] [PDF]

				H. K. Tay and A. J. Melendez Fc{gamma}RI-triggered Generation of Arachidonic Acid and Eicosanoids Requires iPLA2 but Not cPLA2 in Human Monocytic Cells J. Biol. Chem., May 21, 2004; 279(21): 22505 - 22513. [Abstract] [Full Text] [PDF]