title: MnSODtg mice control myocardial inflammatory and oxidative stress and remodeling responses elicited in chronic Chagas disease.
abstract: BACKGROUND
  We utilized genetically modified mice equipped with a variable capacity to scavenge mitochondrial and cellular reactive oxygen species to investigate the pathological significance of oxidative stress in Chagas disease.
  
  
  RESULTS
  C57BL/6 mice (wild type, MnSODtg, MnSOD+/-, GPx1-/-) were infected with Trypanosoma cruzi and harvested during the chronic disease phase. Chronically infected mice exhibited a substantial increase in plasma levels of inflammatory markers (nitric oxide, myeloperoxidase), lactate dehydrogenase, and myocardial levels of inflammatory infiltrate and oxidative adducts (malondialdehyde, carbonyls, 3-nitrotyrosine) in the order of wild type = MnSOD+/- > GPx1-/- > MnSODtg. Myocardial mitochondrial damage was pronounced and associated with a > 50% decline in mitochondrial DNA content in chronically infected wild-type and GPx1(-/-) mice. Imaging of intact heart for cardiomyocytes and collagen by the nonlinear optical microscopy techniques of multiphoton fluorescence/second harmonic generation showed a significant increase in collagen (> 10-fold) in chronically infected wild-type mice, whereas GPx1-/- mice exhibited a basal increase in collagen that did not change during the chronic phase. Chronically infected MnSODtg mice exhibited a marginal decline in mitochondrial DNA content and no changes in collagen signal in the myocardium. P47phox-/- mice lacking phagocyte-generated reactive oxygen species sustained a low level of myocardial oxidative stress and mitochondrial DNA damage in response to Trypanosoma cruzi infection. Yet chronically infected p47phox-/- mice exhibited increase in myocardial inflammatory and remodeling responses, similar to that noted in chronically infected wild-type mice.
  
  
  CONCLUSIONS
  Inhibition of oxidative burst of phagocytes was not sufficient to prevent pathological cardiac remodeling in Chagas disease. Instead, enhancing the mitochondrial reactive oxygen species scavenging capacity was beneficial in controlling the inflammatory and oxidative pathology and the cardiac remodeling responses that are hallmarks of chronic Chagas disease.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX.
authors.forename: Monisha
authors.initials: M
authors.lastname: Dhiman
authors.forename: Xianxiu
authors.initials: X
authors.lastname: Wan
authors.forename: Vsevolod L
authors.initials: VL
authors.lastname: Popov
authors.forename: Gracie
authors.initials: G
authors.lastname: Vargas
authors.forename: Nisha Jain
authors.initials: NJ
authors.lastname: Garg
mesh_terms: D000818:Animals; D002598:Chagas Cardiomyopathy / Q000378:metabolism*; D002908:Chronic Disease; D051379:Mice; D008810:Mice, Inbred C57BL; D009205:Myocarditis / Q000378:metabolism*; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D013482:Superoxide Dismutase
keywords: Chagas disease; Trypanosoma cruzi; cardiac remodeling; mice (MnSODtg, GPx1-/-, P47phox-/-); multiphoton microscopy; oxidative stress; second harmonic generation microscopy