title: Apelin-APJ signaling is a critical regulator of endothelial MEF2 activation in cardiovascular development.
abstract: BACKGROUND
  The peptide ligand apelin and its receptor APJ constitute a signaling pathway with numerous effects on the cardiovascular system, including cardiovascular development in model organisms such as xenopus and zebrafish.
  
  
  OBJECTIVE
  This study aimed to characterize the embryonic lethal phenotype of the Apj-/- mice and to define the involved downstream signaling targets.
  
  
  RESULTS
  We report the first characterization of the embryonic lethality of the Apj-/- mice. More than half of the expected Apj-/- embryos died in utero because of cardiovascular developmental defects. Those succumbing to early embryonic death had markedly deformed vasculature of the yolk sac and the embryo, as well as poorly looped hearts with aberrantly formed right ventricles and defective atrioventricular cushion formation. Apj-/- embryos surviving to later stages demonstrated incomplete vascular maturation because of a deficiency of vascular smooth muscle cells and impaired myocardial trabeculation and ventricular wall development. The molecular mechanism implicates a novel, noncanonical signaling pathway downstream of apelin-APJ involving Gα13, which induces histone deacetylase (HDAC) 4 and HDAC5 phosphorylation and cytoplasmic translocation, resulting in activation of myocyte enhancer factor 2. Apj-/- mice have greater endocardial Hdac4 and Hdac5 nuclear localization and reduced expression of the myocyte enhancer factor 2 (MEF2) transcriptional target Krüppel-like factor 2. We identify a number of commonly shared transcriptional targets among apelin-APJ, Gα13, and MEF2 in endothelial cells, which are significantly decreased in the Apj-/- embryos and endothelial cells.
  
  
  CONCLUSIONS
  Our results demonstrate a novel role for apelin-APJ signaling as a potent regulator of endothelial MEF2 function in the developing cardiovascular system.
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA.
authors.forename: Yujung
authors.initials: Y
authors.lastname: Kang
authors.forename: Jongmin
authors.initials: J
authors.lastname: Kim
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Anderson
authors.forename: Jingxia
authors.initials: J
authors.lastname: Wu
authors.forename: Scott R
authors.initials: SR
authors.lastname: Gleim
authors.forename: Ramendra K
authors.initials: RK
authors.lastname: Kundu
authors.forename: Danielle L
authors.initials: DL
authors.lastname: McLean
authors.forename: Jun-dae
authors.initials: JD
authors.lastname: Kim
authors.forename: Hyekyung
authors.initials: H
authors.lastname: Park
authors.forename: Suk-won
authors.initials: SW
authors.lastname: Jin
authors.forename: John
authors.initials: J
authors.lastname: Hwa
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
authors.forename: Hyung J
authors.initials: HJ
authors.lastname: Chun
mesh_terms: D021581:Active Transport, Cell Nucleus; D054392:Adipokines; D000818:Animals; D000073861:Apelin; D000075244:Apelin Receptors; D018376:Cardiovascular Abnormalities / Q000196:embryology* / Q000235:genetics; D002319:Cardiovascular System / Q000196:embryology*; D004699:Endocardium / Q000196:embryology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D005318:Fetal Heart / Q000002:abnormalities; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D005804:Genes, Lethal; D006655:Histone Deacetylases / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D064326:MEF2 Transcription Factors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018006:Myogenic Regulatory Factors / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D054392:Adipokines; D000073861:Apelin; D000075244:Apelin Receptors; C402826:Apln protein, mouse; C491285:Aplnr protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D064326:MEF2 Transcription Factors; C578036:Mef2a protein, mouse; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; D043562:Receptors, G-Protein-Coupled; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases; D044365:GTP-Binding Protein alpha Subunits, G12-G13
keywords: APJ; Apelin; G proteins; Gα13; HDAC4; HDAC5; MEF2A; MEF2C; developmental biology