Moon 2016 J Biol Chem

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Moon SH, Mancuso DJ, Sims HF, Liu X, Nguyen AL, Yang K, Guan S, Dilthey BG, Jenkins CM, Weinheimer CJ, Kovacs A, Abendschein D, Gross RW (2016) Cardiac myocyte-specific knock-out of calcium-independent phospholipase A2Ξ³ (iPLA2Ξ³) decreases oxidized fatty acids during ischemia/reperfusion and reduces infarct size. J Biol Chem 291:19687-700.

Β» PMID: 27453526

Moon SH, Mancuso DJ, Sims HF, Liu X, Nguyen AL, Yang K, Guan S, Dilthey BG, Jenkins CM, Weinheimer CJ, Kovacs A, Abendschein D, Gross RW (2016) J Biol Chem

Abstract: Calcium-independent phospholipase A2Ξ³ (iPLA2Ξ³) 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 iPLA2Ξ³ in cardiac myocytes, we generated cardiac myocyte-specific iPLA2Ξ³ knock-out (CMiPLA2Ξ³KO) mice by removing the exon encoding the active site serine (Ser-477). Hearts of CMiPLA2Ξ³KO mice exhibited normal hemodynamic function, glycerophospholipid molecular species composition, and normal rates of mitochondrial respiration and ATP production. In contrast, CMiPLA2Ξ³KO 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 CMiPLA2Ξ³KO 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, CMiPLA2Ξ³KO 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 iPLA2Ξ³, these results are consistent with salvage of myocardium after I/R by iPLA2Ξ³ 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.

Β© 2016 by The American Society for Biochemistry and Molecular Biology, Inc. β€’ Keywords: Docosanoid, Eicosanoid, Lipidomics, Mitochondrial membrane potential, Mitochondrial permeability transition (MPT), Myocardial infarction, Phospholipase

β€’ O2k-Network Lab: US MO St Louis Gross RW

Labels: MiParea: Respiration, mt-Membrane, Genetic knockout;overexpression 

Stress:Ischemia-reperfusion  Organism: Mouse  Tissue;cell: Heart  Preparation: Isolated mitochondria 

Regulation: ATP production, mt-Membrane potential  Coupling state: LEAK, OXPHOS  Pathway: F, N, S, NS, Other combinations, ROX  HRR: Oxygraph-2k, TPP 


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