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Hypoxia-driven Hand1 expression controls changes in cardiac metabolism around birth in mice

Presented at the Neonatal Society 2011 Autumn Meeting.

Breckenridge RA, Neary MT, Bennett M, Kotecha S, Griffin J, Mohun TJ

MRC National Institute for Medical Research and University College London, UK

Background: Little is known about the changes occurring in the heart at birth. Immediately following birth, cardiac output rapidly increases, and to facilitate this, the predominant mode of cardiac energy generation shifts from glycolysis to β-oxidation of lipid. This is of relevance to adult cardiac failure, as energy metabolism in failing hearts shifts back to glycolysis. Currently, control of cardiac energy substrate selection is incompletely understood.

The basic-helix-loop-helix transcription factor Hand1 has been implicated in cardiac development, and levels of Hand1 RNA are altered in several types of cardiac failure, all of which are associated with metabolic remodelling.

Methods: Here we show that cardiac Hand1 RNA levels fall rapidly after birth. We have developed a mouse cardiac specific inducible transgenic system to prevent this downregulation. The hearts of Hand1 overxpressing neonates were analysed using Episcopic reconstruction microscopy, Affymetrix RNA expression analysis, RT-PCR and lipidomics.

Results: Prevention of the postnatal fall in cardiac Hand1 transcription in transgenic neonatal mice results in a lethal phenotype of cardiac rupture and lipid droplet accumulation. We observe alterations in gene expression, cardiac acyl-carnitine metabolism and overall lipid metabolism consistent with reduced fatty acid mitochondrial import.

Conclusion: We speculate that Hand1 transcription is regulated by hypoxia signaling and thus link ambient oxygen concentration to metabolic substrate selection. This is a novel function for Hand1, which has been implicated in control of development of the heart, placenta and neural tube-all processes that are known to be in some way influenced by hypoxia signalling.

Corresponding author: rbrecke@nimr.mrc.ac.uk

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