G Protein-Coupled Receptor APJ and Its Ligand Apelin Act Downstream of Cripto to Specify Embryonic Stem Cells Toward the Cardiac Lineage Through Extracellular Signal-Regulated Kinase/p70S6 Kinase Signaling Pathway

Abstract

T he earliest event in cardiogenesis is commitment of mesodermal cells to a cardiogenic fate and their migration into the anterolateral region of the embryo during gastrulation. 1 It is therefore important to understand how mesodermal cells are instructed to assume a cardiac fate to elucidate the molecular mechanisms later in heart development. In mammals, these instructive events are largely unknown. Their identification could provide insights into pathways governing cell lineage specification and differentiation, including transcription factor network and extracellular cues that activate them. 2 In addition, understanding early cardiogenesis is of particular interest because cardiomyocyte loss from damage in mammals is largely irreversible and frequently underlies impaired cardiac function in individuals with heart disease. Although there are still multiple barriers to successful regenerative therapies for cardiac disease using embryonic or adult stem cells, cell-based therapeutic approaches remain a valuable goal, particularly when using strategies that do not cross species barriers. 3,4 In this light, embryonic stem cells (ESCs), which faithfully recapitulate early stages of cardiac cell commitment and differentiation, provide a powerful model for investigating how best to control the earliest events in mammalian cardiomyogenesis and ultimately enhance differentiation efficiency.Proteins essential for heart induction have been studied extensively in ESCs, which includes Wnt/␤-catenin, transforming growth factor-␤ family, bone morphogenetic proteins and Cripto. [5][6][7] Cripto is a glycosylphosphatidylinositolanchored multifunctional protein that is involved in the activation of a complex network of signaling pathways both in development and tumorigenesis. 8,9 Cripto stimulates signaling by the transforming growth factor ␤-family member Nodal or related ligands growth/differentiation factor (GDF)1 and -3, 10,11 through activin type IB (activin receptor-like kinase [ALK]-4) and activin type IIB serine/threonine kinase receptors. 10,12,13 Besides its well-documented stimulatory effect on the canonical Nodal-GDF1-3/ALK-4/Smad2 pathway, Nodal/ALK-4 -independent Cripto activities have also been described. 9,14 Notably, recent data highlight a novel role of Cripto as Activin/transforming growth factor-␤ antagonist. 15,16 Original received September 16, 2008; resubmission received May 21, 2009; revised resubmission received June 22, 2009; accepted June 23, 2009. From the Stem Cell Fate Laboratory (C.D., E.L., S.I., O.G., G.M.), Institute of Genetics and Biophysics "A. Buzzati-Traverso," Consiglio Nazionale delle Ricerche, Naples, Italy; Institute of Genetics and Biophysics "A. Buzzati-Traverso" (C.D., E.L., S.I., O.G., A.M.L., G.L.L., G.M.), Consiglio Nazionale delle Ricerche, Naples, Italy; Vesalius Research Center (M.A., P.C.), VIB, Leuven, Belgium; and Vesalius Research Center (P.C.), Katholieke Universiteit Leuven, Belgium.Correspondence to Gabriella Minchiotti, Institute of Genetics and Biophysics "A. We have ...

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

“…There is also evidence for a role in essential hypertension (EHT) as circulating levels of apelin-12 are decreased in patients with EHT (Sonmez et al 2010). Functionally, the apelinergic system plays a role in the Cripto signalling pathway (which stimulates signalling by the transforming growth factor Nodal or growth/differentiation factors 1 and 3, via activin type IB and type IIB receptors) in mammalian cardiac myogenesis (D'Aniello et al 2009). …”

Apelin Controls Fetal and Neonatal Glucose Homeostasis and Is Altered by Maternal Undernutrition

“…Apelin and APJ mRNAs are expressed in heart, lung, placenta, mammary gland, several regions of the central nervous system, adipocytes, and the gastrointestinal tract (5,6). Depending on the cell type studied, APJ activation results in the activation of several intracellular effectors such as extracellular signalregulated kinases, protein kinase B (PKB or Akt), and p70S6 kinase and in the inhibition of cAMP production (7,8).…”

Apelin Enhances Cardiac Neovascularization After Myocardial Infarction by Recruiting Aplnr+ Circulating Cells

“…19 -21 Apelin signaling has been shown to be involved in the regulation of blood pressure, 22,23 cardiac contractility, 24,25 and cardiac differentiation. 26,27 In addition, apelin/Aplnr signaling is associated with retinal blood vessel formation and tumor angiogenesis. 17,28,29 The marked upregulation of both apelin and Aplnr after hypoxic insult in adult animals 30,31 also suggest a role in ischemia-driven vasculogenesis.…”