Department of Pathology, Saint Louis University School of Medicine, St Louis, Missouri, USA.
Infect Immun. 2013 Jul;81(7):2278-87. doi: 10.1128/IAI.00497-12. Epub 2013 Feb 19.
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.
心肌病是恰加斯病的严重并发症，由原生动物寄生虫克氏锥虫引起。寄生虫通常感染心肌细胞，导致炎症介质的释放，包括类二十烷酸。我们实验室最近的一项研究表明，钙非依赖性磷脂酶 A2γ（iPLA2γ）占兔心室肌细胞中 PLA2 活性的大部分，负责花生四烯酸（AA）和前列腺素 E2（PGE2）的释放。因此，我们假设心脏 iPLA2γ 有助于克氏锥虫感染中的类二十烷酸的产生。用溴烯醇内酯（BEL）的 R 或 S 对映异构体分别抑制同工型 iPLA2γ 或 iPLA2β，表明 iPLA2γ 是永生的鼠心肌细胞（HL-1 细胞）中的主要同工型。用凝血酶刺激 HL-1 细胞，凝血酶是与恰加斯病中小血栓形成有关的丝氨酸蛋白酶，也是 iPLA2 的已知激活剂，可增加 AA 和 PGE2 的释放，并伴有血小板激活因子（PAF）的产生。同样，随着时间的推移，克氏锥虫感染导致 AA 和 PGE2 的释放增加，用（R）-BEL 预处理可抑制这种释放。此外，与野生型（WT）小鼠相比，感染克氏锥虫的 iPLA2γ 敲除（KO）小鼠的存活率较低，组织寄生虫感染增加，这表明 iPLA2γ-KO 小鼠比 WT 小鼠更容易感染。感染后，WT 小鼠的 iPLA2 活性显著增加，而 iPLA2γ-KO 小鼠的心肌 iPLA2 活性没有改变，产生的 PGE2 减少。总之，这些研究表明，克氏锥虫感染激活心肌细胞 iPLA2γ，导致 AA 和 PGE2 释放增加，这些介质可能对宿主在急性感染期间的存活至关重要。因此，这些研究表明，iPLA2γ 在恰加斯病的急性阶段发挥心脏保护作用。
