title: The absence of myocardial calcium-independent phospholipase A2γ results in impaired prostaglandin E2 production and decreased survival in mice with acute Trypanosoma cruzi infection.
abstract: Cardiomyopathy is a serious complication of Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi. The parasite often infects cardiac myocytes, causing the release of inflammatory mediators, including eicosanoids. A recent study from our laboratory demonstrated that calcium-independent phospholipase A2γ (iPLA2γ) accounts for the majority of PLA2 activity in rabbit ventricular myocytes and is responsible for arachidonic acid (AA) and prostaglandin E2 (PGE2) release. Thus, we hypothesized that cardiac iPLA2γ contributes to eicosanoid production in T. cruzi infection. Inhibition of the isoform iPLA2γ or iPLA2β, with the R or S enantiomer of bromoenol lactone (BEL), respectively, demonstrated that iPLA2γ is the predominant isoform in immortalized mouse cardiac myocytes (HL-1 cells). Stimulation of HL-1 cells with thrombin, a serine protease associated with microthrombus formation in Chagas' disease and a known activator of iPLA2, increased AA and PGE2 release, accompanied by platelet-activating factor (PAF) production. Similarly, T. cruzi infection resulted in increased AA and PGE2 release over time that was inhibited by pretreatment with (R)-BEL. Further, T. cruzi-infected iPLA2γ-knockout (KO) mice had lower survival rates and increased tissue parasitism compared to wild-type (WT) mice, suggesting that iPLA2γ-KO mice were more susceptible to infection than WT mice. A significant increase in iPLA2 activity was observed in WT mice following infection, whereas iPLA2γ-KO mice showed no alteration in cardiac iPLA2 activity and produced less PGE2. In summary, these studies demonstrate that T. cruzi infection activates cardiac myocyte iPLA2γ, resulting in increased AA and PGE2 release, mediators that may be essential for host survival during acute infection. Thus, these studies suggest that iPLA2γ plays a cardioprotective role during the acute stage of Chagas' disease.
authors: Department of Pathology, Saint Louis University School of Medicine, St Louis, Missouri, USA. jansharma@ucdavis.edu
authors: Janhavi
authors: J
authors: Sharma
authors: Christopher S
authors: CS
authors: Eickhoff
authors: Daniel F
authors: DF
authors: Hoft
authors: David A
authors: DA
authors: Ford
authors: Richard W
authors: RW
authors: Gross
authors: Jane
authors: J
authors: McHowat
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000096:biosynthesis; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion; D014355:Chagas Disease / Q000378:metabolism* / Q000473:pathology; D015232:Dinoprostone / Q000096:biosynthesis*; D004789:Enzyme Activation; D054522:Group VI Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000469:parasitology; D041681:NIH 3T3 Cells; D009281:Naphthalenes; D010641:Phenotype; D011753:Pyrones; D016019:Survival Analysis; D013917:Thrombin / Q000494:pharmacology; D014349:Trypanosoma cruzi
chemical_list: D009281:Naphthalenes; D011753:Pyrones; D016718:Arachidonic Acid; C068314:6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one; D054522:Group VI Phospholipases A2; C516476:Pla2g6 protein, mouse; D013917:Thrombin; D015232:Dinoprostone; D002118:Calcium