title: ELABELA-APJ axis protects from pressure overload heart failure and angiotensin II-induced cardiac damage.
abstract: OBJECTIVE
  Elabela/Toddler/Apela (ELA) has been identified as a novel endogenous peptide ligand for APJ/Apelin receptor/Aplnr. ELA plays a crucial role in early cardiac development of zebrafish as well as in maintenance of self-renewal of human embryonic stem cells. Apelin was the first identified APJ ligand, and exerts positive inotropic heart effects and regulates the renin-angiotensin system. The aim of this study was to investigate the biological effects of ELA in the cardiovascular system.
  
  
  RESULTS
  Continuous infusion of ELA peptide significantly suppressed pressure overload-induced cardiac hypertrophy, fibrosis and impaired contractility in mice. ELA treatment reduced mRNA expression levels of genes associated with heart failure and fibrosis. The cardioprotective effects of ELA were diminished in APJ knockout mice, indicating that APJ is the key receptor for ELA in the adult heart. Mechanistically, ELA downregulated angiotensin-converting enzyme (ACE) expression in the stressed hearts, whereas it showed little effects on angiotensin-converting enzyme 2 (ACE2) expression, which are distinct from the effects of Apelin. FoxM1 transcription factor, which induces ACE expression in the stressed hearts, was downregulated by ELA but not by Apelin. ELA antagonized angiotensin II-induced hypertension, cardiac hypertrophy, and fibrosis in mice.
  
  
  CONCLUSIONS
  The ELA-APJ axis protects from pressure overload-induced heart failure possibly via suppression of ACE expression and pathogenic angiotensin II signalling. The different effects of ELA and Apelin on the expression of ACE and ACE2 implicate fine-tuned mechanisms for a ligand-induced APJ activation and downstream signalling.
authors.affiliation: Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.|Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, Japan.
authors.forename: Teruki
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.
authors.forename: Chitose
authors.initials: C
authors.lastname: Sato
authors.affiliation: Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kadowaki
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A*STAR, Singapore, Singapore.
authors.forename: Lena
authors.initials: L
authors.lastname: Ho
authors.affiliation: Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Ishida
authors.affiliation: Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
authors.affiliation: Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fukamizu
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A*STAR, Singapore, Singapore.
authors.forename: Bruno
authors.initials: B
authors.lastname: Reversade
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Biological Informatics and Experimental Therapeutics, Akita University Graduate School of Medicine, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Imai
authors.affiliation: Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.|JST-PRESTO, Tokyo, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Kuba
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001011:Aorta / Q000503:physiopathology / Q000601:surgery*; D000075244:Apelin Receptors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D062186:Arterial Pressure; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003250:Constriction; D004195:Disease Models, Animal; D005355:Fibrosis; D000072278:Forkhead Box Protein M1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006333:Heart Failure / Q000209:etiology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D055104:Infusions, Subcutaneous; D008024:Ligands; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D036361:Peptide Hormones / Q000008:administration & dosage / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: C000601133:APELA protein, human; D000075244:Apelin Receptors; C491285:Aplnr protein, mouse; D002316:Cardiotonic Agents; D000072278:Forkhead Box Protein M1; C491524:Foxm1 protein, mouse; D008024:Ligands; D036361:Peptide Hormones; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A
keywords: ACE; ACE2; APJ; Angiotensin; Apelin; Elabela