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.
Highlights
Mitochondrial dysfunction and metabolic remodelling are pivotal in the development of cardiomyopathy
When we reviewed available human dilated cardiomyopathy (DCM) data sets, we found a significant increase in COUP-TFII expression levels (3.2-fold) in 13 myocardial tissues of end-stage non-ischaemic DCM16 (Fig. 1a)
We found that in response to stress imposed by transaortic constriction (TAC), the expression of ventricular COUP-TFII mRNA was induced in mice (Supplementary Fig. 1a)
Summary
Mitochondrial dysfunction and metabolic remodelling are pivotal in the development of cardiomyopathy. COUP-TFII 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 COUPTFII affects mitochondrial function, impairs metabolic remodelling and has a key role in dilated cardiomyopathy. Loss of key members in this regulatory network produces a range of metabolic defects, including heart failure, defective mitochondrial biogenesis and dynamics and maladaptation to cardiac stress in mice[10,11,12,13]. Our results reveal the causative role of COUP-TFII in the development of heart failure
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