Trypanosoma cruzi induces the reactive oxygen species-PARP-1-RelA pathway for up-regulation of cytokine expression in cardiomyocytes

Xueqing Ba, Shivali Gupta, Mercy Davidson, Nisha Garg

Research output: Contribution to journalArticle

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Abstract

In this study, we demonstrate that human cardiomyocytes (AC16) produce reactive oxygen species (ROS) and inflammatory cytokines in response to Trypanosoma cruzi. ROS were primarily produced by mitochondria, some of which diffused to cytosol of infected cardiomyocytes. These ROS resulted in an increase in 8-hydroxyguanine lesions and DNA fragmentation that signaled PARP-1 activation evidenced by poly(ADP-ribose) (PAR) modification of PARP-1 and other proteins in infected cardiomyocytes. Phenyl-α-tert-butylnitrone blocked the mitochondrial ROS (mtROS) formation, DNA damage, and PARP-1 activation in infected cardiomyocytes. Further inhibition studies demonstrated that ROS and PARP-1 signaled TNF-α and IL-1βexpression in infected cardiomyocytes. ROS directly signaled the nuclear translocation of RelA (p65), NF-κB activation, and cytokine gene expression. PARP-1 exhibited no direct interaction with p65 and did not signal its translocation to nuclei in infected cardiomyocytes. Instead, PARP-1 contributed to PAR modification of p65-interacting nuclear proteins and assembly of the NF-κB transcription complex. PJ34 (PARP-1 inhibitor) also prevented mitochondrial poly(ADP-ribosyl)ation (PARylation) and ROS formation. We conclude that T. cruzi-mediated mtROS provide primary stimulus for PARP-1-NF-κB activation and cytokine gene expression in infected cardiomyocytes. PAR modification of mitochondrial membranes then results in a feedback cycle of mtROS formation and DNA damage/PARP-1 activation. ROS, either through direct modulation of cytosolic NF-κB, or via PARP-1-dependent PAR modification of p65-interacting nuclear proteins, contributes to cytokine gene expression. Our results demonstrate a link between ROS and inflammatory responses in cardiomyocytes infected by T. cruzi and provide a clue to the pathomechanism of sustained inflammation in Chagas disease.

Original languageEnglish (US)
Pages (from-to)11596-11606
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number15
DOIs
StatePublished - Apr 9 2010

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Trypanosoma cruzi
Cardiac Myocytes
Reactive Oxygen Species
Up-Regulation
Cytokines
Chemical activation
Gene expression
Nuclear Proteins
Gene Expression
DNA Damage
DNA
Poly Adenosine Diphosphate Ribose
Mitochondria
Chagas Disease
Mitochondrial Membranes
DNA Fragmentation
Transcription
Cytosol
Adenosine Diphosphate
Modulation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Trypanosoma cruzi induces the reactive oxygen species-PARP-1-RelA pathway for up-regulation of cytokine expression in cardiomyocytes. / Ba, Xueqing; Gupta, Shivali; Davidson, Mercy; Garg, Nisha.

In: Journal of Biological Chemistry, Vol. 285, No. 15, 09.04.2010, p. 11596-11606.

Research output: Contribution to journalArticle

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