The Growth Hormone Releasing Hormone Signaling Pathway Governs Cardiomyocyte differentiation in human iPS cells.
Here, we present an O2-independent/HIF-1 (Hypoxia inducible factor-1)-dependent mechanism that regulates developmental and regenerative growth of mammalian cardiomyoblasts. An autocrine feedback mechanism of GH/IGF1/SST (Growth hormone/Insulin-like growth factor 1/Somatostatin) signaling, mediated by GHRH/GHRH-R (Growth hormone-releasing hormone/GHRH-Receptor), is established specifically in NKX2-5 (NK2 Homeobox 5) expressing myocardial cells which affects HIF-1 stability through cAMP (cyclic adenosine monophosphate) or cGMP (cyclic guanosine monophosphate) activity. cAMP-mediated HIF-1 stabilization fuels Warburg metabolism and enhances NKX2-5 expression, limiting the developmental and regenerative growth of cardiomyoblasts. In contrast, cGMP-mediated HIF- 1 inhibition (or knock-out of HIF-1) redirects glycolytically derived citrate toward long-chain saturated fatty acid biosynthesis, leading to enhanced developmental and regenerative growth of cardiomyoblasts. These findings suggest that HIF1-mediated glycolysis serves as a rate-limiting, O2-independent sensor of cardiomyogenesis and that targeting GHRH/GHRH-R signaling could be a therapeutic strategy for regenerating the mammalian heart post-injury. O_FIG O_LINKSMALLFIG WIDTH=177 HEIGHT=200 SRC="FIGDIR/small/478572v3_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@16d3f74org.highwire.dtl.DTLVardef@16115edorg.highwire.dtl.DTLVardef@e68dc7org.highwire.dtl.DTLVardef@660861_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOSummary Figure.C_FLOATNO Cardiomyoblast proliferative capacity is regulated by HIF1-mediated metabolic profile, through an NKX2-5 lineage-specific, O2-independent feedback mechanism. (A), HIF-1 is aerobically regulated through the intracellular activation of cAMP and cGMP in response to a GH1/IGF1/SST feedback mechanism, which activates the GHRH/GHRH-R signaling pathway in NKX2-5+ cardiomyoblasts. Stabilized HIF-1 (e.g. by CoCl2) promotes Warburg metabolism and cell cycle exit, whereas knockout or inhibition (e.g. YC-1) of HIF-1 or cAMP (low-dose metformin) promotes de novo fatty acid synthesis and enhances cardiomyoblast proliferation. (B), HIF-1 aerobic stabilization switches the metabolism towards glycolysis and restricts cardiomyoblast proliferation. Contrariwise, knockout of HIF-1 promotes oxidative metabolism in the Krebs cycle rather than lactate synthesis, thus stimulating the proliferative and regenerative capacity of cardiomyoblasts. C_FIG