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

J. Biol. Chem., Vol. 282, Issue 12, 9216-9227, March 23, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/12/9216    most recent M607307200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted 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 Request Permissions 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?

Dramatic Accumulation of Triglycerides and Precipitation of Cardiac Hemodynamic Dysfunction during Brief Caloric Restriction in Transgenic Myocardium Expressing Human Calcium-independent Phospholipase A₂^*

David J. Mancuso, Xianlin Han, Christopher M. Jenkins, John J. Lehman^¶, Nandakumar Sambandam^¶, Harold F. Sims, Jingyue Yang, Wei Yan, Kui Yang, Karen Green^||, Dana R. Abendschein^¶, Jeffrey E. Saffitz^||, and Richard W. Gross^¶**1

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

Previously, we identified calcium-independent phospholipase A₂ (iPLA₂) with multiple translation initiation sites and dual mitochondrial and peroxisomal localization motifs. To determine the role of iPLA₂ in integrating lipid and energy metabolism, we generated transgenic mice containing the -myosin heavy chain promoter (MHC) placed proximally to the human iPLA₂ coding sequence that resulted in cardiac myocyte-restricted expression of iPLA₂ (TGiPLA₂). TGiPLA₂ mice possessed multiple phenotypes including: 1) a dramatic 35% reduction in myocardial phospholipid mass in both the fed and mildly fasted states; 2) a marked accumulation of triglycerides during brief caloric restriction that represented 50% of total myocardial lipid mass; and 3) acute fasting-induced hemodynamic dysfunction. Biochemical characterization of the TGiPLA₂ protein expressed in cardiac myocytes demonstrated over 25 distinct isoforms by two-dimensional SDS-PAGE Western analysis. Immunohistochemistry identified iPLA₂ in the peroxisomal and mitochondrial compartments in both wild type and transgenic myocardium. Electron microscopy revealed the presence of loosely packed and disorganized mitochondrial cristae in TGiPLA₂ mice that were accompanied by defects in mitochondrial function. Moreover, markedly elevated levels of 1-hydroxyl-2-arachidonoyl-sn-glycero-3-phosphocholine and 1-hydroxyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine were prominent in the TGiPLA₂ myocardium identifying the production of signaling metabolites by this enzyme in vivo. Collectively, these results identified the participation of iPLA₂ in the remarkable lipid plasticity of myocardium, its role in generating signaling metabolites, and its prominent effects in modulating energy storage and utilization in myocardium in different metabolic contexts.

Received for publication, August 1, 2006 , and in revised form, December 18, 2006.

^* This work was supported by Grant 5PO1HL57278-10 from the National Institutes of Health. 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.

¹ To whom correspondence should be addressed: Washington University School of Medicine, Division of Bioorganic Chemistry and Molecular Pharmacology, 660 South Euclid Ave., Campus Box 8020, St. Louis, MO 63110. Tel.: 314-362-2690; Fax: 314-362-1402; E-mail: rgross{at}wustl.edu.

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

This article has been cited by other articles:

				C. M. Jenkins, A. Cedars, and R. W. Gross Eicosanoid signalling pathways in the heart Cardiovasc Res, May 1, 2009; 82(2): 240 - 249. [Abstract] [Full Text] [PDF]

				P. C. Kienesberger, M. Oberer, A. Lass, and R. Zechner Mammalian patatin domain containing proteins: a family with diverse lipolytic activities involved in multiple biological functions J. Lipid Res., April 1, 2009; 50(Supplement): S63 - S68. [Abstract] [Full Text] [PDF]

				A. Gubern, M. Barcelo-Torns, J. Casas, D. Barneda, R. Masgrau, F. Picatoste, J. Balsinde, M. A. Balboa, and E. Claro Lipid Droplet Biogenesis Induced by Stress Involves Triacylglycerol Synthesis That Depends on Group VIA Phospholipase A2 J. Biol. Chem., February 27, 2009; 284(9): 5697 - 5708. [Abstract] [Full Text] [PDF]

				P. Rastogi, D. M. Young, and J. McHowat Tryptase activates calcium-independent phospholipase A2 and releases PGE2 in airway epithelial cells Am J Physiol Lung Cell Mol Physiol, November 1, 2008; 295(5): L925 - L932. [Abstract] [Full Text] [PDF]

				M. Schlame Thematic Review Series: Glycerolipids. Cardiolipin synthesis for the assembly of bacterial and mitochondrial membranes J. Lipid Res., August 1, 2008; 49(8): 1607 - 1620. [Abstract] [Full Text] [PDF]

				D. J. Mancuso, H. F. Sims, X. Han, C. M. Jenkins, S. P. Guan, K. Yang, S. H. Moon, T. Pietka, N. A. Abumrad, P. H. Schlesinger, et al. Genetic Ablation of Calcium-independent Phospholipase A2{gamma} Leads to Alterations in Mitochondrial Lipid Metabolism and Function Resulting in a Deficient Mitochondrial Bioenergetic Phenotype J. Biol. Chem., November 30, 2007; 282(48): 34611 - 34622. [Abstract] [Full Text] [PDF]