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

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.

Metabolic reprogramming from glycolysis to amino acid utilization in cardiac HIF1α deficient mice

“…We have previously described the existence of metabolic territories in the embryonic myocardium with an enhanced glycolytic signature in the compact myocardium by E12.5 [12]. Here we show that the main affected functions in the Hif1a/Nkx2.5 mutant hearts were related with glucose catabolic processes and transport ( Fig.…”

“…HIF1α is expressed in the developing myocardium, with a temporal dynamics along midgestation [12,13,15]. We and others have described the heterogeneous regional distribution of HIF1 signaling with high HIF1α levels in the compact myocardium in contrast with low expression in the trabeculae [12,13,15]. HIF1 has been proposed to regulate cardiomyocyte proliferation during cardiogenesis.…”

“…We have previously reported that sustained HIF1 signaling in the embryonic myocardium results in severe alterations of mitochondrial amount and function [12]. To evaluate the bioenergetics adaptations in response to lack of cardiac HIF1 activation we investigated mitochondrial network and activity in Hif1a/NKx2.5 mutants.…”

“…This metabolic switch is coincident with the change in oxygen levels after birth [23]. However, a recent report from our group has shown that metabolic shift towards fatty acid oxidation (FAO) occurs earlier during development at around E14.5, through a mechanism dependent of a decrease in HIF1 signaling in the embryonic myocardium [12]. Despite of the importance of glucose and FA as cardiac energy sources, amino acids can also be used as bioenergetics fuel.…”

“…In addition to the existence of hypoxic areas during heart development [4,8], it has been described that chronic exposure of pregnant females to 8% oxygen causes embryonic myocardial thinning, epicardial detachment and death [9] and global deletion of different components of the hypoxia pathway display cardiovascular phenotypes [10]. Moreover, geneticbased overactivation of HIF signaling by inactivation of Vhl gene in cardiac cells using different drivers (Mlc2vCre, Nkx2.5Cre) causes morphological, metabolic and functional cardiac alterations that results in embryonic lethality [11,12]. On the other hand, loss of function models based on conditional deletion of Hif1a gene in cardiac populations also causes several cardiac alterations during embryogenesis [13][14][15], indicating that a controlled balance in the oxygen levels and hypoxia signaling is required for proper heart development.…”