title: Increased COUP-TFII expression in adult hearts induces mitochondrial dysfunction resulting in heart failure.
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.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130, USA.
authors.forename: San-Pin
authors.initials: SP
authors.lastname: Wu
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Chung-Yang
authors.initials: CY
authors.lastname: Kao
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Leiming
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: Department of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Taraka R
authors.initials: TR
authors.lastname: Donti
authors.affiliation: Department of Internal Medicine, University of Texas Medical School at Houston, Houston, Texas 77030, USA.
authors.forename: Romain
authors.initials: R
authors.lastname: Harmancey
authors.affiliation: Department of Internal Medicine, University of Texas Medical School at Houston, Houston, Texas 77030, USA.
authors.forename: Hernan G
authors.initials: HG
authors.lastname: Vasquez
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Brett H
authors.initials: BH
authors.lastname: Graham
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Bellen
authors.affiliation: Department of Internal Medicine, University of Texas Medical School at Houston, Houston, Texas 77030, USA.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Taegtmeyer
authors.affiliation: Department of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Ching-Pin
authors.initials: CP
authors.lastname: Chang
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tsai
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Sophia Y
authors.initials: SY
authors.lastname: Tsai
mesh_terms: D000818:Animals; D051837:COUP Transcription Factor II / Q000235:genetics* / Q000378:metabolism; D019703:Calcineurin / Q000235:genetics; D002311:Cardiomyopathy, Dilated / Q000235:genetics; D019069:Cell Respiration / Q000235:genetics; D004452:Echocardiography; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism*; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018384:Oxidative Stress; D010101:Oxygen Consumption; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D051837:COUP Transcription Factor II; D045222:Electron Transport Chain Complex Proteins; D017382:Reactive Oxygen Species; D019703:Calcineurin