Increased COUP-TFII expression in adult hearts induces mitochondrial dysfunction resulting in heart failure

San Pin Wu, Chung Yang Kao, Leiming Wang, Chad J. Creighton, Jin Yang, Taraka R. Donti, Romain Harmancey, Hernan G. Vasquez, Brett H. Graham, Hugo J. Bellen, Heinrich Taegtmeyer, Ching-Pin Chang, Ming Jer Tsai, Sophia Y. Tsai

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Mitochondrial dysfunction and metabolic remodelling are pivotal in the development of cardiomyopathy. Here, we show that myocardial COUP-TFII overexpression causes heart failure in mice, suggesting a causal effect of elevated COUP-TFII levels on development of dilated cardiomyopathy. COUP-TFII represses genes critical for mitochondrial electron transport chain enzyme activity, oxidative stress detoxification and mitochondrial dynamics, resulting in increased levels of reactive oxygen species and lower rates of oxygen consumption in mitochondria. COUP-TFII also suppresses the metabolic regulator PGC-1 network and decreases the expression of key glucose and lipid utilization genes, leading to a reduction in both glucose and oleate oxidation in the hearts. These data suggest that COUP-TFII affects mitochondrial function, impairs metabolic remodelling and has a key role in dilated cardiomyopathy. Last, COUP-TFII haploinsufficiency attenuates the progression of cardiac dilation and improves survival in a calcineurin transgenic mouse model, indicating that COUP-TFII may serve as a therapeutic target for the treatment of dilated cardiomyopathy.

Original languageEnglish
Article number8245
JournalNature Communications
Volume6
DOIs
StatePublished - Sep 10 2015

Fingerprint

Dilated Cardiomyopathy
glucose
genes
mice
Heart Failure
Genes
oxygen consumption
Glucose
Detoxification
enzyme activity
Mitochondria
Oxidative stress
mitochondria
Calcineurin
regulators
Enzyme activity
Oleic Acid
progressions
Mitochondrial Dynamics
lipids

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Wu, S. P., Kao, C. Y., Wang, L., Creighton, C. J., Yang, J., Donti, T. R., ... Tsai, S. Y. (2015). Increased COUP-TFII expression in adult hearts induces mitochondrial dysfunction resulting in heart failure. Nature Communications, 6, [8245]. https://doi.org/10.1038/ncomms9245

Increased COUP-TFII expression in adult hearts induces mitochondrial dysfunction resulting in heart failure. / Wu, San Pin; Kao, Chung Yang; Wang, Leiming; Creighton, Chad J.; Yang, Jin; Donti, Taraka R.; Harmancey, Romain; Vasquez, Hernan G.; Graham, Brett H.; Bellen, Hugo J.; Taegtmeyer, Heinrich; Chang, Ching-Pin; Tsai, Ming Jer; Tsai, Sophia Y.

In: Nature Communications, Vol. 6, 8245, 10.09.2015.

Research output: Contribution to journalArticle

Wu, SP, Kao, CY, Wang, L, Creighton, CJ, Yang, J, Donti, TR, Harmancey, R, Vasquez, HG, Graham, BH, Bellen, HJ, Taegtmeyer, H, Chang, C-P, Tsai, MJ & Tsai, SY 2015, 'Increased COUP-TFII expression in adult hearts induces mitochondrial dysfunction resulting in heart failure', Nature Communications, vol. 6, 8245. https://doi.org/10.1038/ncomms9245
Wu, San Pin ; Kao, Chung Yang ; Wang, Leiming ; Creighton, Chad J. ; Yang, Jin ; Donti, Taraka R. ; Harmancey, Romain ; Vasquez, Hernan G. ; Graham, Brett H. ; Bellen, Hugo J. ; Taegtmeyer, Heinrich ; Chang, Ching-Pin ; Tsai, Ming Jer ; Tsai, Sophia Y. / Increased COUP-TFII expression in adult hearts induces mitochondrial dysfunction resulting in heart failure. In: Nature Communications. 2015 ; Vol. 6.
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