Oxidative Stress Causes Heart Failure with Impaired Mitochondrial Respiration*

  1. Hidetoshi Nojiri ‡ § ,
  2. Takahiko Shimizu ‡ ∥ ,
  3. Masabumi Funakoshi ‡ ** ,
  4. Osamu Yamaguchi ‡‡ ,
  5. Heying Zhou ‡ ,
  6. Satoru Kawakami ‡ ∥ ,
  7. Yutaka Ohta §§ ,
  8. Manabu Sami §§ ,
  9. Toshiaki Tachibana ¶¶ ,
  10. Hiroshi Ishikawa ¶¶ ,
  11. Hisashi Kurosawa § ,
  12. Ronald C. Kahn ∥∥ ,
  13. Kinya Otsu ‡‡ and
  14. Takuji Shirasawa ‡ ∥ ** 1
  1. ‡Research Team for Molecular Biomarkers, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan, the §Department of Orthopedics, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan, **Biological Science, Graduate School of Science, Tokyo Metropolitan University, Hachioji-shi, Tokyo 192-0397, Japan, ‡‡Osaka University Graduated School of Medicine, Suita, Osaka, 565-0871, Japan, §§Fundamental Research Laboratory, Asahi Breweries, Ltd., Moriya-shi, Ibaraki 302-0106, Japan, the ¶¶Department of Anatomy II, Jikei University School of Medicine, Minato-ku, Tokyo 105-8461, Japan, ∥∥Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, Applied Biological Chemistry, United Graduate School of Agricultural Science, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo 183-8509, Japan, and ∥Anti-Aging Science, Inc., Chiyoda-ku, Tokyo 100-0001, Japan
  1. 1 To whom correspondence should be addressed: Research Team for Molecular Biomarkers, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan. Tel.: 81-3-3964-3241; Fax: 81-3-3579-4776; E-mail: sirasawa{at}tmig.or.jp.

Abstract

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 (Formula), 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 Formula 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.

Footnotes

  • ↵ 2 The abbreviations used are: LV, left ventricular; CAG, cytomegalovirus enhancer/chicken β-actin; COX, cytochrome c oxidase; MCK, muscle creatine kinase; SOD, superoxide dismutase; MnTBAP, manganese 5,10,15,20-tetrakis (4-benzoic acid) porphyrin; NF-κB, nuclear factor-κB; OXPHOS, oxidative phosphorylation; PAS, periodic acid-Schiff; ROS, reactive oxygen species; SDH, succinate dehydrogenase; Formula, superoxide; TA, tibialis anterior; PBS, phosphate-buffered saline; MDA, malondialdehyde; TUNEL, terminal dUTP nick-end labeling.

  • ↵* This work was supported by grants from Comprehensive Research on Aging and Health, the Ministry of Health, Labor, and Welfare, and by grants-in-aid for Scientific Research from the Ministry of Education, Science, Culture, Sports, and Technology. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • ↵Graphic The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1.

    • Received March 6, 2006.
    • Revision received July 21, 2006.
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  1. First Published on September 6, 2006 doi: 10.1074/jbc.M602118200 The Journal of Biological Chemistry 281, 33789-33801.
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