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 () and Sophia Y. Tsai ()
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San-Pin Wu: Baylor College of Medicine
Chung-Yang Kao: Baylor College of Medicine
Leiming Wang: Baylor College of Medicine
Chad J. Creighton: Baylor College of Medicine
Jin Yang: Indiana University School of Medicine
Taraka R. Donti: Baylor College of Medicine
Romain Harmancey: University of Texas Medical School at Houston
Hernan G. Vasquez: University of Texas Medical School at Houston
Brett H. Graham: Baylor College of Medicine
Hugo J. Bellen: Baylor College of Medicine
Heinrich Taegtmeyer: University of Texas Medical School at Houston
Ching-Pin Chang: Indiana University School of Medicine
Ming-Jer Tsai: Baylor College of Medicine
Sophia Y. Tsai: Baylor College of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9245

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