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

Author

Listed:
  • San-Pin Wu

    (Baylor College of Medicine
    Adrienne Helis Malvin Medical Research Foundation)

  • Chung-Yang Kao

    (Baylor College of Medicine)

  • Leiming Wang

    (Baylor College of Medicine)

  • Chad J. Creighton

    (Baylor College of Medicine
    Dan L. Duncan Cancer Center, 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
    Program in Developmental Biology, Baylor College of Medicine)

  • Hugo J. Bellen

    (Baylor College of Medicine
    Program in Developmental Biology, 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
    Program in Developmental Biology, Baylor College of Medicine)

  • Sophia Y. Tsai

    (Baylor College of Medicine
    Program in Developmental Biology, Baylor College of Medicine)

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.

Suggested Citation

  • 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 , 2015. "Increased COUP-TFII expression in adult hearts induces mitochondrial dysfunction resulting in heart failure," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9245
    DOI: 10.1038/ncomms9245
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    Cited by:

    1. Thanh Theresa Dinh & Menglan Xiang & Anusha Rajaraman & Yongzhi Wang & Nicole Salazar & Yu Zhu & Walter Roper & Siyeon Rhee & Kevin Brulois & Ed O’Hara & Helena Kiefel & Truc M. Dinh & Yuhan Bi & Dali, 2022. "An NKX-COUP-TFII morphogenetic code directs mucosal endothelial addressin expression," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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