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Dev Cell. 2016 Dec 19;39(6):724-739. doi: 10.1016/j.devcel.2016.11.012.

Myocardial VHL-HIF Signaling Controls an Embryonic Metabolic Switch Essential for Cardiac Maturation.

Author information

1
Myocardial Pathophysiology Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
2
Developmental and Cell Biology Program, CNIC, 28029 Madrid, Spain; CIBER de Enfermedades Respiratorias (CIBERES), Madrid, Spain.
3
Myocardial Pathophysiology Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain; Cardiac Imaging Department, Hospital de La Princesa, 28006 Madrid, Spain.
4
Research Unit, Hospital Santa Cristina, 28009 Madrid, Spain.
5
Developmental and Cell Biology Program, CNIC, 28029 Madrid, Spain; CIBER de Enfermedades Respiratorias (CIBERES), Madrid, Spain; Department of Chemistry and Physics II, Pharmacy School, Universidad Complutense de Madrid, 28040 Madrid, Spain.
6
Developmental and Cell Biology Program, CNIC, 28029 Madrid, Spain.
7
Myocardial Pathophysiology Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain. Electronic address: smartinp@cnic.es.

Abstract

While gene regulatory networks involved in cardiogenesis have been characterized, the role of bioenergetics remains less studied. Here we show that until midgestation, myocardial metabolism is compartmentalized, with a glycolytic signature restricted to compact myocardium contrasting with increased mitochondrial oxidative activity in the trabeculae. HIF1α regulation mirrors this pattern, with expression predominating in compact myocardium and scarce in trabeculae. By midgestation, the compact myocardium downregulates HIF1α and switches toward oxidative metabolism. Deletion of the E3 ubiquitin ligase Vhl results in HIF1α hyperactivation, blocking the midgestational metabolic shift and impairing cardiac maturation and function. Moreover, the altered glycolytic signature induced by HIF1 trabecular activation precludes regulation of genes essential for establishment of the cardiac conduction system. Our findings reveal VHL-HIF-mediated metabolic compartmentalization in the developing heart and the connection between metabolism and myocardial differentiation. These results highlight the importance of bioenergetics in ventricular myocardium specialization and its potential relevance to congenital heart disease.

KEYWORDS:

HIF; VHL; cardiac conduction system; cardiac maturation; glycolysis; heart development; hypoxia; metabolic reprogramming; mitochondria; transcriptional repression

PMID:
27997827
DOI:
10.1016/j.devcel.2016.11.012
[Indexed for MEDLINE]
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