title: Inhibition of NFE2L2-Antioxidant Response Element Pathway by Mitochondrial Reactive Oxygen Species Contributes to Development of Cardiomyopathy and Left Ventricular Dysfunction in Chagas Disease.
abstract: OBJECTIVE
  We investigated the effects of mitochondrial reactive oxygen species (mtROS) on nuclear factor (erythroid 2)-like 2 (NFE2L2) transcription factor activity during Trypanosoma cruzi (Tc) infection and determined whether enhancing the mtROS scavenging capacity preserved the heart function in Chagas disease.
  
  
  RESULTS
  C57BL/6 wild type (WT, female) mice infected with Tc exhibited myocardial loss of mitochondrial membrane potential, complex II (CII)-driven coupled respiration, and ninefold increase in mtROS production. In vitro and in vivo studies showed that Tc infection resulted in an ROS-dependent decline in the expression, nuclear translocation, antioxidant response element (ARE) binding, and activity of NFE2L2, and 35-99% decline in antioxidants' (gamma-glutamyl cysteine synthase [γGCS], heme oxygenase-1 [HO1], glutamate-cysteine ligase modifier subunit [GCLM], thioredoxin (Trx), glutathione S transferase [GST], and NAD(P)H dehydrogenase, quinone 1 [NQO1]) expression. An increase in myocardial and mitochondrial oxidative adducts, myocardial interventricular septum thickness, and left ventricle (LV) mass, a decline in LV posterior wall thickness, and disproportionate synthesis of collagens (COLI/COLIII), αSMA, and SM22α were noted in WT.Tc mice. Overexpression of manganese superoxide dismutase (MnSOD) in cultured cells (HeLa or cardiomyocytes) and MnSODtgmice preserved the NFE2L2 transcriptional activity and antioxidant/oxidant balance, and cardiac oxidative and fibrotic pathology were significantly decreased in MnSODtg.Tc mice. Importantly, echocardiography finding of a decline in LV systolic (stroke volume, cardiac output, ejection fraction) and diastolic (early/late peak filling ratio, myocardial performance index) function in WT.Tc mice was abolished in MnSODtg.Tc mice. Innovation and Conclusion: The mtROS inhibition of NFE2L2/ARE pathway constitutes a key mechanism in signaling the fibrotic gene expression and evolution of chronic cardiomyopathy. Preserving the NFE2L2 activity arrested the mitochondrial and cardiac oxidative stress, cardiac fibrosis, and heart failure in Chagas disease. Antioxid. Redox Signal. 27, 550-566.
authors.affiliation: 1 Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB) , Galveston, Texas.
authors.forename: Jake Jianjun
authors.initials: JJ
authors.lastname: Wen
authors.affiliation: 2 Metabolism Unit, Shriners Hospital for Children , Galveston, Texas.|3 Department of Surgery, University of Texas Medical Branch (UTMB) , Galveston, Texas.
authors.forename: Craig
authors.initials: C
authors.lastname: Porter
authors.affiliation: 1 Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB) , Galveston, Texas.|4 Department of Pathology, University of Texas Medical Branch (UTMB) , Galveston, Texas.|5 Institute for Human Infections and Immunity, University of Texas Medical Branch (UTMB) , Galveston, Texas.
authors.forename: Nisha Jain
authors.initials: NJ
authors.lastname: Garg
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements; D000975:Antioxidants / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics / Q000503:physiopathology*; D014355:Chagas Disease / Q000150:complications* / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000503:physiopathology*
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase
keywords: Chagas disease; LV dysfunction; MnSOD; NFE2L2; Trypanosoma cruzi; cardiac remodeling; mitochondrial respiration