Format

Send to

Choose Destination
Nat Commun. 2015 Sep 10;6:8245. doi: 10.1038/ncomms9245.

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

Author information

1
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
2
Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130, USA.
3
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
4
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
5
Department of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
6
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
7
Department of Internal Medicine, University of Texas Medical School at Houston, Houston, Texas 77030, USA.
8
Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA.

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.

PMID:
26356605
PMCID:
PMC4568566
DOI:
10.1038/ncomms9245
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center