Phenyl-α-tert-butyl-nitrone and Benzonidazole Treatment Controlled the Mitochondrial Oxidative Stress and Evolution of Cardiomyopathy in Chronic Chagasic Rats

Jian Jun Wen, Shivali Gupta, Zhangjun Guan, Monisha Dhiman, David Condon, Charles Lui, Nisha Garg

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2499-2508
Number of pages10
JournalJournal of the American College of Cardiology
Volume55
Issue number22
DOIs
StatePublished - Jun 1 2010

Fingerprint

Takotsubo Cardiomyopathy
Oxidative Stress
Trypanosoma cruzi
Parasites
Pathology
Antiparasitic Agents
Chagas Disease
Brain Natriuretic Peptide
Atrial Natriuretic Factor
Electron Transport
benzonidazole
phenyl-N-tert-butylnitrone
Malondialdehyde
NADP
Peroxidase
Sprague Dawley Rats
Actins
Reactive Oxygen Species
Oxidoreductases
Respiration

Keywords

  • antioxidant
  • benzonidazole
  • Chagas disease
  • mitochondrial oxidative stress
  • Trypanosoma cruzi

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Phenyl-α-tert-butyl-nitrone and Benzonidazole Treatment Controlled the Mitochondrial Oxidative Stress and Evolution of Cardiomyopathy in Chronic Chagasic Rats. / Wen, Jian Jun; Gupta, Shivali; Guan, Zhangjun; Dhiman, Monisha; Condon, David; Lui, Charles; Garg, Nisha.

In: Journal of the American College of Cardiology, Vol. 55, No. 22, 01.06.2010, p. 2499-2508.

Research output: Contribution to journalArticle

Wen, Jian Jun ; Gupta, Shivali ; Guan, Zhangjun ; Dhiman, Monisha ; Condon, David ; Lui, Charles ; Garg, Nisha. / Phenyl-α-tert-butyl-nitrone and Benzonidazole Treatment Controlled the Mitochondrial Oxidative Stress and Evolution of Cardiomyopathy in Chronic Chagasic Rats. In: Journal of the American College of Cardiology. 2010 ; Vol. 55, No. 22. pp. 2499-2508.
@article{5aecb295bf86449892a8e8c2218b83ab,
title = "Phenyl-α-tert-butyl-nitrone and Benzonidazole Treatment Controlled the Mitochondrial Oxidative Stress and Evolution of Cardiomyopathy in Chronic Chagasic Rats",
abstract = "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.",
keywords = "antioxidant, benzonidazole, Chagas disease, mitochondrial oxidative stress, Trypanosoma cruzi",
author = "Wen, {Jian Jun} and Shivali Gupta and Zhangjun Guan and Monisha Dhiman and David Condon and Charles Lui and Nisha Garg",
year = "2010",
month = "6",
day = "1",
doi = "10.1016/j.jacc.2010.02.030",
language = "English (US)",
volume = "55",
pages = "2499--2508",
journal = "Journal of the American College of Cardiology",
issn = "0735-1097",
publisher = "Elsevier USA",
number = "22",

}

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

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 - antioxidant

KW - benzonidazole

KW - Chagas disease

KW - mitochondrial oxidative stress

KW - Trypanosoma cruzi

UR - http://www.scopus.com/inward/record.url?scp=77952518968&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77952518968&partnerID=8YFLogxK

U2 - 10.1016/j.jacc.2010.02.030

DO - 10.1016/j.jacc.2010.02.030

M3 - Article

VL - 55

SP - 2499

EP - 2508

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

SN - 0735-1097

IS - 22

ER -