LRRFIP2 modulates the response to hypoxia during embryonic cardiogenesis

Abstract

Oxygen is crucial for appropriate embryonic and fetal development, including cardiogenesis. The heart is the first organ formed in the embryo and is required to provide oxygen and nutrients to all cells in the body. Embryonic cardiogenesis is a complex process finely regulated and prone to congenital malformations. It takes place in a hypoxic environment that activates the HIF-1 signaling pathway which mediates cellular and systemic adaptations to low oxygen levels. Since inhibition or overactivation of the HIF-1 signaling pathway in the myocardium lead to severe cardiac malformations and embryonic lethality, it is important that the cellular response to hypoxia be precisely regulated. While many gene regulatory networks involved in embryonic cardiogenesis have been characterized in detail, the modulation of the response of cardiomyocytes (CM) to hypoxia has remained less studied. We identified LRRFIP2 as a new negative cofactor of HIF-1. Indeed, we have shown that the absence of Lrrfip2 expression in a mouse KI model led to an enhance of many HIF-1 target genes including Igfbp3, Bnip3 and Ndufa4l2 in embryonic CM during development. As results, the absence of Lrrfip2 led to the inhibition of the PI3K/Akt survival pathway, growth defects, mitochondrial dysfunction and to a precocious maturation of the embryonic CMs. Altogether, these defects led to the formation of a smaller heart unable to provide sufficient oxygen to the embryo and finally to a severe hypoxia and a precocious lethality. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/472540v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1cb5836org.highwire.dtl.DTLVardef@10c7b97org.highwire.dtl.DTLVardef@86263aorg.highwire.dtl.DTLVardef@137da51_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LILRRFIP2 regulates negatively the HIF-1 activity C_LIO_LILrrfip2 deletion leads to an embryonic lethality between E11.5 and E13.5 C_LIO_LILRRFIP2 controls ROS production and CM maturation C_LI