The Absence of Myocardial Calcium-Independent Phospholipase A2γ Results in Impaired Prostaglandin E2 Production and Decreased Survival in Mice with Acute Trypanosoma cruzi Infection

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 A(2)gamma (iPLA(2)gamma) accounts for the majority of PLA(2) activity in rabbit ventricular myocytes and is responsible for arachidonic acid (AA) and prostaglandin E-2 (PGE(2)) release. Thus, we hypothesized that cardiac iPLA(2)gamma contributes to eicosanoid production in T. cruzi infection. Inhibition of the isoform iPLA(2)gamma or iPLA(2)beta, with the R or S enantiomer of bromoenol lactone (BEL), respectively, demonstrated that iPLA(2)gamma 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 iPLA(2), increased AA and PGE(2) release, accompanied by platelet-activating factor (PAF) production. Similarly, T. cruzi infection resulted in increased AA and PGE(2) release over time that was inhibited by pretreatment with (R)-BEL. Further, T. cruzi-infected iPLA(2)gamma-knockout (KO) mice had lower survival rates and increased tissue parasitism compared to wild-type (WT) mice, suggesting that iPLA(2)gamma-KO mice were more susceptible to infection than WT mice. A significant increase in iPLA(2) activity was observed in WT mice following infection, whereas iPLA(2)gamma-KO mice showed no alteration in cardiac iPLA(2) activity and produced less PGE(2). In summary, these studies demonstrate that T. cruzi infection activates cardiac myocyte iPLA(2)gamma, resulting in increased AA and PGE(2) release, mediators that may be essential for host survival during acute infection. Thus, these studies suggest that iPLA(2)gamma plays a cardioprotective role during the acute stage of Chagas' disease.