title: Cardiac Myocyte-specific Knock-out of Calcium-independent Phospholipase A2γ (iPLA2γ) Decreases Oxidized Fatty Acids during Ischemia/Reperfusion and Reduces Infarct Size.
abstract: Calcium-independent phospholipase A2γ (iPLA2γ) is a mitochondrial enzyme that produces lipid second messengers that facilitate opening of the mitochondrial permeability transition pore (mPTP) and contribute to the production of oxidized fatty acids in myocardium. To specifically identify the roles of iPLA2γ in cardiac myocytes, we generated cardiac myocyte-specific iPLA2γ knock-out (CMiPLA2γKO) mice by removing the exon encoding the active site serine (Ser-477). Hearts of CMiPLA2γKO mice exhibited normal hemodynamic function, glycerophospholipid molecular species composition, and normal rates of mitochondrial respiration and ATP production. In contrast, CMiPLA2γKO mice demonstrated attenuated Ca(2+)-induced mPTP opening that could be rapidly restored by the addition of palmitate and substantially reduced production of oxidized polyunsaturated fatty acids (PUFAs). Furthermore, myocardial ischemia/reperfusion (I/R) in CMiPLA2γKO mice (30 min of ischemia followed by 30 min of reperfusion in vivo) dramatically decreased oxidized fatty acid production in the ischemic border zones. Moreover, CMiPLA2γKO mice subjected to 30 min of ischemia followed by 24 h of reperfusion in vivo developed substantially less cardiac necrosis in the area-at-risk in comparison with their WT littermates. Furthermore, we found that membrane depolarization in murine heart mitochondria was sensitized to Ca(2+) by the presence of oxidized PUFAs. Because mitochondrial membrane depolarization and calcium are known to activate iPLA2γ, these results are consistent with salvage of myocardium after I/R by iPLA2γ loss of function through decreasing mPTP opening, diminishing production of proinflammatory oxidized fatty acids, and attenuating the deleterious effects of abrupt increases in calcium ion on membrane potential during reperfusion.
authors.affiliation: From the Division of Bioorganic Chemistry and Molecular Pharmacology, Departments of Medicine.
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Moon
authors.affiliation: From the Division of Bioorganic Chemistry and Molecular Pharmacology, Departments of Medicine.
authors.forename: David J
authors.initials: DJ
authors.lastname: Mancuso
authors.affiliation: From the Division of Bioorganic Chemistry and Molecular Pharmacology, Departments of Medicine.
authors.forename: Harold F
authors.initials: HF
authors.lastname: Sims
authors.affiliation: From the Division of Bioorganic Chemistry and Molecular Pharmacology, Departments of Medicine.
authors.forename: Xinping
authors.initials: X
authors.lastname: Liu
authors.affiliation: Center for Cardiovascular Research, Washington University School of Medicine, Saint Louis, Missouri 63110 and.
authors.forename: Annie L
authors.initials: AL
authors.lastname: Nguyen
authors.affiliation: From the Division of Bioorganic Chemistry and Molecular Pharmacology, Departments of Medicine.
authors.forename: Kui
authors.initials: K
authors.lastname: Yang
authors.affiliation: From the Division of Bioorganic Chemistry and Molecular Pharmacology, Departments of Medicine.
authors.forename: Shaoping
authors.initials: S
authors.lastname: Guan
authors.affiliation: From the Division of Bioorganic Chemistry and Molecular Pharmacology, Departments of Medicine.
authors.forename: Beverly Gibson
authors.initials: BG
authors.lastname: Dilthey
authors.affiliation: From the Division of Bioorganic Chemistry and Molecular Pharmacology, Departments of Medicine.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Jenkins
authors.affiliation: Center for Cardiovascular Research, Washington University School of Medicine, Saint Louis, Missouri 63110 and.
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Weinheimer
authors.affiliation: Center for Cardiovascular Research, Washington University School of Medicine, Saint Louis, Missouri 63110 and.
authors.forename: Attila
authors.initials: A
authors.lastname: Kovacs
authors.affiliation: Center for Cardiovascular Research, Washington University School of Medicine, Saint Louis, Missouri 63110 and.
authors.forename: Dana
authors.initials: D
authors.lastname: Abendschein
authors.affiliation: From the Division of Bioorganic Chemistry and Molecular Pharmacology, Departments of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, Saint Louis, Missouri 63110 and Developmental Biology, and the Department of Chemistry, Washington University, Saint Louis, Missouri 63130 rgross@wustl.edu.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Gross
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D054522:Group VI Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000201:enzymology* / Q000235:genetics; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000235:genetics; D009206:Myocardium / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000201:enzymology*; D009928:Organ Specificity; D010084:Oxidation-Reduction
chemical_list: D005231:Fatty Acids, Unsaturated; D054522:Group VI Phospholipases A2; C516476:Pla2g6 protein, mouse; D002118:Calcium
keywords: docosanoid; eicosanoid; lipidomics; mitochondrial membrane potential; mitochondrial permeability transition (MPT); myocardial infarction; phospholipase