The Absence of Myocardial Calcium-Independent Phospholipase A ₂ γ Results in Impaired Prostaglandin E ₂ 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 A 2 ␥ (iPLA 2 ␥) 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 ␥ contributes to eicosanoid production in T. cruzi infection. Inhibition of the isoform iPLA 2 ␥ or iPLA 2 ␤, with the R or S enantiomer of bromoenol lactone (BEL), respectively, demonstrated that iPLA 2 ␥ 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 ␥-knockout (KO) mice had lower survival rates and increased tissue parasitism compared to wild-type (WT) mice, suggesting that iPLA 2 ␥-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 ␥-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 ␥, 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 ␥ plays a cardioprotective role during the acute stage of Chagas' disease.

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

“…Chagas' disease is caused by protozoan parasite Trypanosoma cruzi , which infects cardiac myocytes promoting release of infl ammatory mediators such as eicosanoids. Inhibition of iPLA 2 ␥ attenuated AA and PGE 2 release and platelet-activating factor (PAF) production from HL-1 cardiac myocytes infected with T. cruzi ( 83 ), and these effects were alleviated by pretreatment with R -BEL. Consistent with a protective role of iPLA 2 ␥ in this process, the survival rates were lowered and tissue parasitism amplifi ed in T. cruziinfected iPLA 2 ␥ -null mice, suggesting that iPLA 2 ␥ activity affords protection against acute state cardiomyopathy in Chagas' disease ( 83 ).…”

“…Inhibition of iPLA 2 ␥ attenuated AA and PGE 2 release and platelet-activating factor (PAF) production from HL-1 cardiac myocytes infected with T. cruzi ( 83 ), and these effects were alleviated by pretreatment with R -BEL. Consistent with a protective role of iPLA 2 ␥ in this process, the survival rates were lowered and tissue parasitism amplifi ed in T. cruziinfected iPLA 2 ␥ -null mice, suggesting that iPLA 2 ␥ activity affords protection against acute state cardiomyopathy in Chagas' disease ( 83 ). In contrast, iPLA 2 ␥ -defi ciency has been shown to increase bleeding time and provide resistance to thromboembolism ( 84 ), raising the possibility of targeting iPLA 2 ␥ for antithrombotic drug development.…”

Inhibition of Cyclooxygenase-1 and Cyclooxygenase-2 Impairs Trypanosoma cruzi Entry into Cardiac Cells and Promotes Differential Modulation of the Inflammatory Response

“…A recent study demonstrated that cardiac calcium-independent phospholipase A 2 ␥ (iPLA 2 ␥) is responsible for AA and prostaglandin E 2 (PGE 2 ) release in T. cruzi infection (11). PGs are oxygenated lipid mediators formed from the 6 essential fatty acid AA.…”

“…cruzi induces upregulation of nitric oxide (NO) production in cardiomyocytes along with an upregulation in the levels of interleukin-6 (IL-6), IL-1␤, tumor necrosis factor alpha (TNF-␣), and transforming growth factor ␤ (TGF-␤) (8)(9)(10)(11)(12)(13). The resulting acute myocarditis is characterized by an intense inflammatory response typified by upregulation of inflammatory mediators, such as cytokines, chemokines, inducible nitric oxide synthase (iNOS), and endothelin (7), and also eicosanoids (10), which are essential elements to the defensive reaction in cardiac tissue (4), and it can also result in cardiac hypertrophy (8,9).…”

COX-2 rs20417 Polymorphism Is Associated with Stroke and White Matter Disease

“…Treatment with prostaglandin agonist misoprostol decreased infarct size in a murine ischemic stroke model(26). In a knock-out mouse model with acute Chagas disease infection, cardiac myocytes with low PGE2 levels had decreased survival when compared to wild-type mice with normal PGE2 levels(27). In human chronic cardiac Chagas disease, one study found that anti-muscarinic acetylcholine receptor antibodies activate COX-2 gene expression and PGE2 production(28).…”