Document Detail

Oxidative stress causes heart failure with impaired mitochondrial respiration.
MedLine Citation:
PMID:  16959785     Owner:  NLM     Status:  MEDLINE    
Elderly people insidiously manifest the symptoms of heart failure, such as dyspnea and/or physical disabilities in an age-dependent manner. Although previous studies suggested that oxidative stress plays a pathological role in the development of heart failure, no direct evidence has been documented so far. In order to investigate the pathological significance of oxidative stress in the heart, we generated heart/muscle-specific manganese superoxide dismutase-deficient mice. The mutant mice developed progressive congestive heart failure with specific molecular defects in mitochondrial respiration. In this paper, we showed for the first time that the oxidative stress caused specific morphological changes of mitochondria, excess formation of superoxide (O(2)(*)(-)), reduction of ATP, and transcriptional alterations of genes associated with heart failure in respect to cardiac contractility. Accordingly, administration of a superoxide dismutase mimetic significantly ameliorated the symptoms. These results implied that O(2)(*)(-) generated in mitochondria played a pivotal role in the development and progression of heart failure. We here present a bona fide model for human cardiac failure with oxidative stress valuable for therapeutic interventions.
Hidetoshi Nojiri; Takahiko Shimizu; Masabumi Funakoshi; Osamu Yamaguchi; Heying Zhou; Satoru Kawakami; Yutaka Ohta; Manabu Sami; Toshiaki Tachibana; Hiroshi Ishikawa; Hisashi Kurosawa; Ronald C Kahn; Kinya Otsu; Takuji Shirasawa
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-09-06
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  281     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2006 Nov 
Date Detail:
Created Date:  2006-10-30     Completed Date:  2006-12-11     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  33789-801     Citation Subset:  IM    
Research Team for Molecular Biomarkers, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan.
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MeSH Terms
Disease Progression
Gene Expression Regulation
Heart Diseases / genetics,  metabolism*,  pathology*
Lipid Peroxidation
Mice, Knockout
Microscopy, Electron, Transmission
Mitochondria, Heart / metabolism*
Muscle, Skeletal / cytology,  metabolism
Oxidative Stress*
Reactive Oxygen Species / metabolism
Superoxide Dismutase / deficiency,  genetics,  metabolism
Transcription, Genetic / genetics
Reg. No./Substance:
0/Reactive Oxygen Species; EC Dismutase; EC dismutase 2

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