The Absence of Myocardial Calcium-Independent Phospholipase A2γ Results in Impaired Prostaglandin E2Production and Decreased Survival in Mice with Acute Trypanosoma cruzi Infection

Abstract

ABSTRACTCardiomyopathy is a serious complication of Chagas' disease, caused by the protozoan parasiteTrypanosoma 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 PLA2activity 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 inT. cruziinfection. Inhibition of the isoform iPLA2γ or iPLA2β, with theRorSenantiomer 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 PGE2release, accompanied by platelet-activating factor (PAF) production. Similarly,T. cruziinfection resulted in increased AA and PGE2release 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 iPLA2activity was observed in WT mice following infection, whereas iPLA2γ-KO mice showed no alteration in cardiac iPLA2activity and produced less PGE2. In summary, these studies demonstrate thatT. cruziinfection activates cardiac myocyte iPLA2γ, resulting in increased AA and PGE2release, 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.