Cruzipain, a major Trypanosoma cruzi antigen, promotes arginase-2 expression and survival of neonatal mouse cardiomyocytes

Faculty of Chemical Science, National University of Cordoba, Argentina, Córdoba, Cordoba, Argentina
AJP Cell Physiology (Impact Factor: 3.67). 03/2004; 286(2):C206-12. DOI: 10.1152/ajpcell.00282.2003
Source: PubMed

ABSTRACT An intense myocarditis is frequently found in the acute phase of Trypanosoma cruzi infection. Despite the cardiac damage, infected individuals may remain asymptomatic for decades. Thus T. cruzi may directly prevent cardiomyocyte death to keep heart destruction in check. Recently, it has been shown that Schwann cell invasion by T. cruzi, their prime target in the peripheral nervous system, suppressed host cell apoptosis caused by growth factor deprivation. Likewise, the trans-sialidase of T. cruzi reproduced this antiapoptotic activity of the parasite. In this study, we have investigated the effect of cruzipain, another important T. cruzi antigen, on survival and cell death of neonatal BALB/c mouse cardiomyocyte cultures. We have found that cruzipain, as well as T. cruzi infection, promoted survival of cardiomyocytes cultured under serum deprivation. The antiapoptotic effect was mediated by Bcl-2 expression but not by Bcl-xL expression. Because arginase activity is involved in cell differentiation and wound healing in most cell types and it favors parasite growth within the cell, we have further investigated the effect of cruzipain on the regulation of l-arginine metabolic pathways. Our results have revealed that cruzipain enhanced arginase activity and the expression of arginase-2 isoform but failed to induce nitric oxide synthase activity. In addition, the inhibition of arginase activity by NG-hydroxy-l-arginine, abrogated the antiapoptotic action of cruzipain. The results demonstrate that cruzipain may act as a survival factor for cardiomyocytes because it rescued them from apoptosis and stimulated arginase-2.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The haemoflagellate Trypanosoma cruzi is the causative agent of Chagas' disease that occurs in approximately 8 million people in Latin America. Patients infected with T. cruzi frequently suffer of cardiomegaly and may die of myocardial failure. Here we show that T. cruzi trypomastigotes (extracellular form) increased in vitro apoptosis of rat cardiomyocytes. Additionally, we demonstrated that amastigotes (intracellular form), for which a method for purification was established, were also able to induce cardiomyocyte apoptosis. Increase of apoptosis was associated with up-regulation of the apoptotic gene bax by trypomastigotes, while expression of the anti-apoptotic gene bcl-2 was down-regulated by amastigotes. The transcription factor STAT3 but not STAT1 was activated in cardiomyocytes by trypomastigotes. In addition, tlr7 gene expression was up-regulated in cardiomyocytes incubated with trypomastigotes, suggesting that this Toll-like receptor is involved in the intracellular recognition after host cell invasion by T. cruzi. Glycosylphosphatidylinositols purified from trypomastigotes did not induce cardiomyocyte apoptosis and STAT activation but down-regulated tlr7 gene expression. In conclusion, cardiomyopathy observed in Chagas' disease might be in part due to apoptosis of cardiomyocytes induced directly by the parasite.
    Apoptosis 02/2013; 18(6). DOI:10.1007/s10495-013-0822-x · 3.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The early host resistance against Trypanosoma cruzi infection depends on a complex interplay among cytokines, chemical mediators and cells. The major innate immune mechanism against intracellular parasites in phagocytes relies on the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The initial step for ROS production is the generation of superoxide anion catalyzed by the enzyme NADPH oxidase. The phagocyte´s NADPH oxidase is a multiprotein complex, which exists in the dissociated state in resting cells and assembles into the functional complex upon stimulation. Additionally, the high amount production of the RNS nitric oxide (NO) depends on the enzyme nitric oxide synthase induction by cytokines. The combination of superoxide anion and NO yields peroxynitrite, the most parasite-harmful reactive species. The anti-inflammatory and pro-inflammatory cytokine balance modulates the activation and induction of both enzymes. Here we discuss the cellular processes involved in macrophage-mediated host defense against Trypanosoma cruzi, and the implications of ROS, RNS and cytokine regulation in host resistance.


Available from
May 30, 2014