Oxidative stress causes heart failure with impaired mitochondrial respiration.
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.
Nojiri
Hidetoshi
H
Research Team for Molecular Biomarkers, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan.
Shimizu
Takahiko
T
Funakoshi
Masabumi
M
Yamaguchi
Osamu
O
Zhou
Heying
H
Kawakami
Satoru
S
Ohta
Yutaka
Y
Sami
Manabu
M
Tachibana
Toshiaki
T
Ishikawa
Hiroshi
H
Kurosawa
Hisashi
H
Kahn
Ronald C
RC
Otsu
Kinya
K
Shirasawa
Takuji
T
D000818:Animals; D017209:Apoptosis; D018450:Disease Progression; D005786:Gene Expression Regulation; D006331:Heart Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015227:Lipid Peroxidation; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008929:Mitochondria, Heart / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D000099156:Superoxide Dismutase 2
D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2