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@article{Yang:2017:10.1161/CIRCULATIONAHA.116.023218,
author = {Yang, P and Read, C and Kuc, RE and Buonincontri, G and Southwood, M and Torella, R and Upton, PD and Crosby, A and Sawiak, SJ and Carpenter, TA and Glen, RC and Morrell, NW and Maguire, JJ and Davenport, AP},
doi = {10.1161/CIRCULATIONAHA.116.023218},
journal = {Circulation},
pages = {1160--1173},
title = {Elabela/toddler is an endogenous agonist of the apelin APJ receptor in the adult cardiovascular system, and exogenous administration of the peptide compensates for the downregulation of its expression in pulmonary arterial hypertension},
url = {http://dx.doi.org/10.1161/CIRCULATIONAHA.116.023218},
volume = {135},
year = {2017}
}

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TY  - JOUR
AB  - Background—Elabela/Toddler (ELA) is a critical cardiac developmental peptide that acts through the G protein-coupled apelin receptor, despite lack of sequence similarity to the established ligand apelin. Our aim was to investigate the receptor pharmacology, expression pattern and in vivo function of ELA peptides in the adult cardiovascular system, to seek evidence for alteration in pulmonary arterial hypertension (PAH) in which apelin signaling is down-regulated, and to demonstrate attenuation of PAH severity with exogenous administration of ELA in a rat model.Methods—In silico docking analysis, competition binding experiments and down-stream assays were used to characterize ELA receptor binding in human heart and signaling in cells expressing the apelin receptor. ELA expression in human cardiovascular tissues and plasma was determined using RT-qPCR, dual-labelling immunofluorescent staining and immunoassays. Acute cardiac effects of ELA-32 and [Pyr1]apelin-13 were assessed by magnet resonance imaging and cardiac catheterization in anesthetized rats. Cardiopulmonary human and rat tissues from PAH patients and monocrotaline (MCT) and Sugen/hypoxia exposed rats were used to show changes in ELA expression in PAH. The effect of ELA treatment on cardiopulmonary remodeling in PAH was investigated in the MCT rat model.Results—ELA competed for binding of apelin in human heart with overlap for the two peptides indicated by in silico modeling. ELA activated G protein- and Β-arrestin-dependent pathways. We detected ELA expression in human vascular endothelium and plasma. Comparable to apelin, ELA increased cardiac contractility, ejection fraction, cardiac output and elicited vasodilatation in rat in vivo. ELA expression was reduced in cardiopulmonary tissues from PAH patients and PAH rat models, respectively. ELA treatment significantly attenuated elevation of right ventricular systolic pressure and right ventricular hypertrophy and pulmonary vascular re
AU  - Yang,P
AU  - Read,C
AU  - Kuc,RE
AU  - Buonincontri,G
AU  - Southwood,M
AU  - Torella,R
AU  - Upton,PD
AU  - Crosby,A
AU  - Sawiak,SJ
AU  - Carpenter,TA
AU  - Glen,RC
AU  - Morrell,NW
AU  - Maguire,JJ
AU  - Davenport,AP
DO  - 10.1161/CIRCULATIONAHA.116.023218
EP  - 1173
PY  - 2017///
SN  - 0009-7322
SP  - 1160
TI  - Elabela/toddler is an endogenous agonist of the apelin APJ receptor in the adult cardiovascular system, and exogenous administration of the peptide compensates for the downregulation of its expression in pulmonary arterial hypertension
T2  - Circulation
UR  - http://dx.doi.org/10.1161/CIRCULATIONAHA.116.023218
UR  - https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.116.023218
UR  - http://hdl.handle.net/10044/1/44643
VL  - 135
ER  -

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