TY - JOUR
T1 - ELABELA-APJ axis protects from pressure overload heart failure and angiotensin II-induced cardiac damage
AU - Sato, Teruki
AU - Sato, Chitose
AU - Kadowaki, Ayumi
AU - Watanabe, Hiroyuki
AU - Ho, Lena
AU - Ishida, Junji
AU - Yamaguchi, Tomokazu
AU - Kimura, Akinori
AU - Fukamizu, Akiyoshi
AU - Penninger, Josef M.
AU - Reversade, Bruno
AU - Ito, Hiroshi
AU - Imai, Yumiko
AU - Kuba, Keiji
N1 - Funding Information:
K.K. is supported by the Kaken [Grant nos. 26293050 and 15K15304] from Japanese Ministry of Science, the PRESTO from JST, and Takeda Foundation. T.S. is supported by the Kaken [Grant nos. 30733422 and 16K19013] from Japanese Ministry of Science. J.M.P. is supported by the Foundation Leducq. B.R. and L.H. are funded by a Strategic Positioning Fund on Genetic Orphan Diseases from the Biomedical Research Council, A*STAR, Singapore.
Publisher Copyright:
© The Author 2017. Published on behalf of the European Society of Cardiology. All rights reserved.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - 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.
AB - 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.
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U2 - 10.1093/cvr/cvx061
DO - 10.1093/cvr/cvx061
M3 - Article
C2 - 28371822
AN - SCOPUS:85027346845
SN - 0008-6363
VL - 113
SP - 760
EP - 769
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 7
ER -