MnSOD^tg Mice Control Myocardial Inflammatory and Oxidative Stress and Remodeling Responses Elicited in Chronic Chagas Disease

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. Methods and Results--C57BL/6 mice (wild type, MnSOD^tg, 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^-/- > MnSOD^tg. 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. P47^phox-/- 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 p47^phox-/- 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.