Teruki Sato1,2, Chitose Sato1, Ayumi Kadowaki1, Hiroyuki Watanabe2, Lena Ho3, Junji Ishida4, Tomokazu Yamaguchi1, Akinori Kimura5, Akiyoshi Fukamizu4, Josef M Penninger6, Bruno Reversade3, Hiroshi Ito2, Yumiko Imai7, Keiji Kuba1,8. 1. Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan. 2. Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, Japan. 3. Institute of Medical Biology, Human Genetics and Embryology Laboratory, A*STAR, Singapore, Singapore. 4. Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, Japan. 5. Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. 6. IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria. 7. Department of Biological Informatics and Experimental Therapeutics, Akita University Graduate School of Medicine, Japan. 8. JST-PRESTO, Tokyo, Japan.
Abstract
AIMS: 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. METHODS AND 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: 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. METHODS AND 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Steven J Forrester; George W Booz; Curt D Sigmund; Thomas M Coffman; Tatsuo Kawai; Victor Rizzo; Rosario Scalia; Satoru Eguchi Journal: Physiol Rev Date: 2018-07-01 Impact factor: 37.312
Authors: Bikram Sharma; Lena Ho; Gretchen Hazel Ford; Heidi I Chen; Andrew B Goldstone; Y Joseph Woo; Thomas Quertermous; Bruno Reversade; Kristy Red-Horse Journal: Dev Cell Date: 2017-09-07 Impact factor: 12.270
Authors: Cai Read; Duuamene Nyimanu; Thomas L Williams; David J Huggins; Petra Sulentic; Robyn G C Macrae; Peiran Yang; Robert C Glen; Janet J Maguire; Anthony P Davenport Journal: Pharmacol Rev Date: 2019-10 Impact factor: 25.468