TY - JOUR
T1 - Phenyl-α-tert-butyl-nitrone and Benzonidazole Treatment Controlled the Mitochondrial Oxidative Stress and Evolution of Cardiomyopathy in Chronic Chagasic Rats
AU - Wen, Jian Jun
AU - Gupta, Shivali
AU - Guan, Zhangjun
AU - Dhiman, Monisha
AU - Condon, David
AU - Lui, Charles
AU - Garg, Nisha Jain
N1 - Funding Information:
This work was supported by a grant ( AI054578 ) from the National Institutes of Health/National Institute of Allergy and Infectious Disease to Dr. Garg.
PY - 2010/6/1
Y1 - 2010/6/1
N2 - Objectives: The purpose of this study was to determine the pathological importance of oxidative stress-induced injurious processes in chagasic heart dysfunction. Background: Trypanosoma cruzi-induced inflammatory pathology and a feedback cycle of mitochondrial dysfunction and oxidative stress may contribute to Chagas disease. Methods: Sprague-Dawley rats were infected with T. cruzi and treated with phenyl-α-tert-butylnitrone (PBN), an antioxidant, and/or benzonidazole (BZ), an antiparasitic agent. We monitored myocardial parasite burden, oxidative adducts, mitochondrial complex activities, respiration, and adenosine triphosphate synthesis rates, and inflammatory and cardiac remodeling responses during disease development. The cardiac hemodynamics was determined for all rats. Results: Benzonidazole (not PBN) decreased the parasite persistence and immune adverse events (proinflammatory cytokine expression, β-nicotinamide adenine dinucleotide phosphate oxidase and myeloperoxidase activities, and inflammatory infiltrate) in chronically infected hearts. PBN ± BZ (not BZ alone) decreased the mitochondrial reactive oxygen species level, oxidative adducts (malonyldialdehyde, 4-hydroxynonenal, carbonyls), hypertrophic gene expression (atrial natriuretic peptide, B-type natriuretic peptide, α-skeletal actin), and collagen deposition and preserved the respiratory chain efficiency and energy status in chronically infected hearts. Subsequently, LV dysfunction was prevented in PBN ± BZ-treated chagasic rats. Conclusions: BZ treatment after the acute stage decreased the parasite persistence and inflammatory pathology. Yet, oxidative adducts, mitochondrial dysfunction, and remodeling responses persisted and contributed to declining cardiac function in chagasic rats. Combination treatment (PBN + BZ) was beneficial in arresting the T. cruzi-induced inflammatory and oxidative pathology and chronic heart failure in chagasic rats.
AB - Objectives: The purpose of this study was to determine the pathological importance of oxidative stress-induced injurious processes in chagasic heart dysfunction. Background: Trypanosoma cruzi-induced inflammatory pathology and a feedback cycle of mitochondrial dysfunction and oxidative stress may contribute to Chagas disease. Methods: Sprague-Dawley rats were infected with T. cruzi and treated with phenyl-α-tert-butylnitrone (PBN), an antioxidant, and/or benzonidazole (BZ), an antiparasitic agent. We monitored myocardial parasite burden, oxidative adducts, mitochondrial complex activities, respiration, and adenosine triphosphate synthesis rates, and inflammatory and cardiac remodeling responses during disease development. The cardiac hemodynamics was determined for all rats. Results: Benzonidazole (not PBN) decreased the parasite persistence and immune adverse events (proinflammatory cytokine expression, β-nicotinamide adenine dinucleotide phosphate oxidase and myeloperoxidase activities, and inflammatory infiltrate) in chronically infected hearts. PBN ± BZ (not BZ alone) decreased the mitochondrial reactive oxygen species level, oxidative adducts (malonyldialdehyde, 4-hydroxynonenal, carbonyls), hypertrophic gene expression (atrial natriuretic peptide, B-type natriuretic peptide, α-skeletal actin), and collagen deposition and preserved the respiratory chain efficiency and energy status in chronically infected hearts. Subsequently, LV dysfunction was prevented in PBN ± BZ-treated chagasic rats. Conclusions: BZ treatment after the acute stage decreased the parasite persistence and inflammatory pathology. Yet, oxidative adducts, mitochondrial dysfunction, and remodeling responses persisted and contributed to declining cardiac function in chagasic rats. Combination treatment (PBN + BZ) was beneficial in arresting the T. cruzi-induced inflammatory and oxidative pathology and chronic heart failure in chagasic rats.
KW - Chagas disease
KW - Trypanosoma cruzi
KW - antioxidant
KW - benzonidazole
KW - mitochondrial oxidative stress
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U2 - 10.1016/j.jacc.2010.02.030
DO - 10.1016/j.jacc.2010.02.030
M3 - Article
C2 - 20510218
AN - SCOPUS:77952518968
SN - 0735-1097
VL - 55
SP - 2499
EP - 2508
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 22
ER -