Trypanosoma cruziInfection and Nuclear Factor Kappa B Activation Prevent Apoptosis in Cardiac Cells

Abstract

Studies of cardiac pathology and heart failure have implicated cardiomyocyte apoptosis as a critical determinant of disease. Recent evidence indicates that the intracellular protozoan parasite Trypanosoma cruzi, which causes heart disease in chronically infected individuals, impinges on host apoptotic pathways in a cell type-dependent manner. T. cruzi infection of isolated neuronal cells and cardiomyocytes protects against apoptotic cell death, whereas apoptosis is triggered in T cells in T. cruzi-infected animals. In this study, we demonstrate that the ability of T. cruzi to protect cardiac cells in vitro from apoptosis triggered by a combination of tumor necrosis factor alpha and serum reduction correlates with the presence of intracellular parasites and involves activation of host cell NF-B. We further demonstrate that the apoptotic block diminishes activation of caspase 3. The ability of T. cruzi to prevent apoptosis of infected cardiomyocytes is likely to play an important role in establishment of persistent infection in the heart while minimizing potential damage and remodeling that is associated with cardiomyocyte apoptosis in cardiovascular disease.

Selective Impairment of Nuclear Factor-κB-Dependent Gene Transcription in Adult Cardiomyocytes

“…34 On the other hand, data from various groups have stressed the relevance of this activation of the NF-B pathway to mediate cell protection and function under pathological circumstances; for example, in animals infected with Trypanosoma cruzi, there is a selective impairment of the apoptotic response to TNF-␣ in cardiomyocytes and neurons via the activation of the NF-B pathway, and this response seems to be specific because T cells undergo apoptosis after infection. 35,36 In agreement with this view, hypertrophic heart can be considered as a condition in which NF-B is activated and cells are protected against apoptotic death.…”

Interferon-γ and other inflammatory mediators in cardiomyocyte signaling during Chagas disease cardiomyopathy

“…The establishment of a long-term infection in the heart and the development of a cardiomyopathy condition are directly related to the ability of T. cruzi to infect and persist within cardiomyocytes during the acute phase of infection [33,34] . Cardiomyocytes are differentiated cells that respond to T.cruzi infection by initiating adaptive strategies.…”

“…These strategies can involve immunological and non-immunological events. For example, during T.cruzi infection cardiomyocytes reactivate an embryonic gene expression pattern [8] (e.g., an increase in expression of atrial natriuretic factor), inhibit apoptosis [34] , increase cell size by producing myofibrils (cardiac myosin heavy chain, several α-actin isoforms, smooth muscle myosin, actin-binding proteins, and collagen) and initiate a hypertrophic program, that are not related to an immunological response to the parasite [7] . However, these cells are actively integrated in the inflammatory process and can secrete chemokines such as C-C chemokine monocyte chemotactic protein 1 (JE/MCP-1/CCL2), chemokine (C-C motif) ligand 5 (RANTES/CCL5), keratinocyte chemoattractant (KC/CXCL3), macrophage inflammatory protein (MIP-2/CXCL2), Mig/CXCL9, and cytokineresponsive gene-2 (Crg-2/CXCL10), and the cytokines TNF-α, IL-1β and inducible NO synthase (iNOS) [35] .…”

Cloning and functional identification of a novel BCA3 splice

“…NF-kB regulates the transcription of many genes involved in immunoinflammatory responses, cell proliferation, and survival, and thus plays crucial roles in the pathogenesis of many diseases. Importantly, NF-kB is involved in many cellular processes (Burleigh and Woolsey, 2002), including interleukin (IL)-1b production (Petersen et al, 2005), invasion (Hall et al, 2000), and inhibition of apoptosis of parasite-infected cells (Petersen et al, 2006). BCA3, the catalytic subunit of PKA (PKAc), and the p65 subunit of NF-kB form a cytosolic complex that may be modulated through PKA activators.…”