Upregulation of Nox4 by hypertrophic stimuli promotes apoptosis and mitochondrial dysfunction in cardiac myocytes

Tetsuro Ago, Junya Kuroda, Jayashree Pain, Cexiong Fu, Hong Li, Junichi Sadoshima

Research output: Contribution to journalArticlepeer-review

419 Citations (Scopus)


RATIONALE: NADPH oxidases are a major source of superoxide (Õ2) in the cardiovascular system. The function of Nox4, a member of the Nox family of NADPH oxidases, in the heart is poorly understood. OBJECTIVE: The goal of this study was to elucidate the role of Nox4 in mediating oxidative stress and growth/death in the heart. METHODS AND RESULTS: Expression of Nox4 in the heart was increased in response to hypertrophic stimuli and aging. Neither transgenic mice with cardiac specific overexpression of Nox4 (Tg-Nox4) nor those with catalytically inactive Nox4 (Tg-Nox4-P437H) showed an obvious baseline cardiac phenotype at young ages. Tg-Nox4 gradually displayed decreased left ventricular (LV) function with enhanced O2 production in the heart, which was accompanied by increased apoptosis and fibrosis at 13 to 14 months of age. On the other hand, the level of oxidative stress was attenuated in Tg-Nox4-P437H. Although the size of cardiac myocytes was significantly greater in Tg-Nox4 than in nontransgenic, the LV weight/tibial length was not significantly altered in Tg-Nox4 mice. Overexpression of Nox4 in cultured cardiac myocytes induced apoptotic cell death but not hypertrophy. Nox4 is primarily localized in mitochondria and upregulation of Nox4 enhanced both rotenone-and diphenyleneiodonium-sensitive O2 production in mitochondria. Cysteine residues in mitochondrial proteins, including aconitase and NADH dehydrogenases, were oxidized and their activities decreased in Tg-Nox4. CONCLUSIONS: Upregulation of Nox4 by hypertrophic stimuli and aging induces oxidative stress, apoptosis and LV dysfunction, in part because of mitochondrial insufficiency caused by increased O2 production and consequent cysteine oxidation in mitochondrial proteins.

Original languageEnglish
Pages (from-to)1253-1264
Number of pages12
JournalCirculation research
Issue number7
Publication statusPublished - Apr 2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine


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