Dramatic accumulation of triglycerides and precipitation of cardiac hemodynamic dysfunction during brief caloric restriction in transgenic myocardium expressing human calcium-independent phospholipase A 2γ

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, Richard W. Gross

Research output: Contribution to journalArticle

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Abstract

Previously, we identified calcium-independent phospholipase A 2γ(iPLA2γ) with multiple translation initiation sites and dual mitochondrial and peroxisomal localization motifs. To determine the role of iPLA2γ in integrating lipid and energy metabolism, we generated transgenic mice containing the α-myosin heavy chain promoter (αMHC) placed proximally to the human iPLA 2γ coding sequence that resulted in cardiac myocyte-restricted expression of iPLA2γ (TGiPLA2γ). TGiPLA 2γ 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 TGiPLA2γ protein expressed in cardiac myocytes demonstrated over 25 distinct isoforms by two-dimensional SDS-PAGE Western analysis. Immunohistochemistry identified iPLA2γ 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 TGiPLA2γ 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 TGiPLA 2γ myocardium identifying the production of signaling metabolites by this enzyme in vivo. Collectively, these results identified the participation of iPLA2γ 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.

Original languageEnglish (US)
Pages (from-to)9216-9227
Number of pages12
JournalJournal of Biological Chemistry
Volume282
Issue number12
DOIs
StatePublished - Mar 23 2007
Externally publishedYes

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Caloric Restriction
Phospholipases A
Hemodynamics
Myocardium
Triglycerides
Calcium
Metabolites
Cardiac Myocytes
Hydroxyl Radical
Calcium-Independent Phospholipase A2
Lipids
Phosphorylcholine
Myosin Heavy Chains
Lipid Metabolism
Energy storage
Energy Metabolism
Electron microscopy
Transgenic Mice
Plasticity
Polyacrylamide Gel Electrophoresis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Dramatic accumulation of triglycerides and precipitation of cardiac hemodynamic dysfunction during brief caloric restriction in transgenic myocardium expressing human calcium-independent phospholipase A 2γ. / Mancuso, David J.; Han, Xianlin; Jenkins, Christopher M.; Lehman, John J.; Sambandam, Nandakumar; Sims, Harold F.; Yang, Jingyue; Yan, Wei; Yang, Kui; Green, Karen; Abendschein, Dana R.; Saffitz, Jeffrey E.; Gross, Richard W.

In: Journal of Biological Chemistry, Vol. 282, No. 12, 23.03.2007, p. 9216-9227.

Research output: Contribution to journalArticle

Mancuso, David J. ; Han, Xianlin ; Jenkins, Christopher M. ; Lehman, John J. ; Sambandam, Nandakumar ; Sims, Harold F. ; Yang, Jingyue ; Yan, Wei ; Yang, Kui ; Green, Karen ; Abendschein, Dana R. ; Saffitz, Jeffrey E. ; Gross, Richard W. / Dramatic accumulation of triglycerides and precipitation of cardiac hemodynamic dysfunction during brief caloric restriction in transgenic myocardium expressing human calcium-independent phospholipase A 2γ. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 12. pp. 9216-9227.
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abstract = "Previously, we identified calcium-independent phospholipase A 2γ(iPLA2γ) with multiple translation initiation sites and dual mitochondrial and peroxisomal localization motifs. To determine the role of iPLA2γ in integrating lipid and energy metabolism, we generated transgenic mice containing the α-myosin heavy chain promoter (αMHC) placed proximally to the human iPLA 2γ coding sequence that resulted in cardiac myocyte-restricted expression of iPLA2γ (TGiPLA2γ). TGiPLA 2γ 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 TGiPLA2γ protein expressed in cardiac myocytes demonstrated over 25 distinct isoforms by two-dimensional SDS-PAGE Western analysis. Immunohistochemistry identified iPLA2γ 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 TGiPLA2γ 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 TGiPLA 2γ myocardium identifying the production of signaling metabolites by this enzyme in vivo. Collectively, these results identified the participation of iPLA2γ 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.",
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T1 - Dramatic accumulation of triglycerides and precipitation of cardiac hemodynamic dysfunction during brief caloric restriction in transgenic myocardium expressing human calcium-independent phospholipase A 2γ

AU - Mancuso, David J.

AU - Han, Xianlin

AU - Jenkins, Christopher M.

AU - Lehman, John J.

AU - Sambandam, Nandakumar

AU - Sims, Harold F.

AU - Yang, Jingyue

AU - Yan, Wei

AU - Yang, Kui

AU - Green, Karen

AU - Abendschein, Dana R.

AU - Saffitz, Jeffrey E.

AU - Gross, Richard W.

PY - 2007/3/23

Y1 - 2007/3/23

N2 - Previously, we identified calcium-independent phospholipase A 2γ(iPLA2γ) with multiple translation initiation sites and dual mitochondrial and peroxisomal localization motifs. To determine the role of iPLA2γ in integrating lipid and energy metabolism, we generated transgenic mice containing the α-myosin heavy chain promoter (αMHC) placed proximally to the human iPLA 2γ coding sequence that resulted in cardiac myocyte-restricted expression of iPLA2γ (TGiPLA2γ). TGiPLA 2γ 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 TGiPLA2γ protein expressed in cardiac myocytes demonstrated over 25 distinct isoforms by two-dimensional SDS-PAGE Western analysis. Immunohistochemistry identified iPLA2γ 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 TGiPLA2γ 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 TGiPLA 2γ myocardium identifying the production of signaling metabolites by this enzyme in vivo. Collectively, these results identified the participation of iPLA2γ 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.

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