| First Author | Moon SH | Year | 2016 |
| Journal | J Biol Chem | Volume | 291 |
| Issue | 37 | Pages | 19687-700 |
| PubMed ID | 27453526 | Mgi Jnum | J:236927 |
| Mgi Id | MGI:5810230 | Doi | 10.1074/jbc.M116.740597 |
| Citation | Moon SH, et al. (2016) Cardiac Myocyte-specific Knock-out of Calcium-independent Phospholipase A2gamma (iPLA2gamma) Decreases Oxidized Fatty Acids during Ischemia/Reperfusion and Reduces Infarct Size. J Biol Chem 291(37):19687-700 |
| abstractText | Calcium-independent phospholipase A2gamma (iPLA2gamma) 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 iPLA2gamma in cardiac myocytes, we generated cardiac myocyte-specific iPLA2gamma knock-out (CMiPLA2gammaKO) mice by removing the exon encoding the active site serine (Ser-477). Hearts of CMiPLA2gammaKO mice exhibited normal hemodynamic function, glycerophospholipid molecular species composition, and normal rates of mitochondrial respiration and ATP production. In contrast, CMiPLA2gammaKO 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 CMiPLA2gammaKO 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, CMiPLA2gammaKO 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 iPLA2gamma, these results are consistent with salvage of myocardium after I/R by iPLA2gamma 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. |
