Abstract 13911: ELABELA/Toddler (Apela), is an Endogenous Ligand of the Human Apelin Receptor and is Reduced in Pulmonary Arterial Hypertension
Introduction: The apelin receptor is proposed as a therapeutic target in pulmonary arterial hypertension (PAH). The apelin peptide knockout mouse does not recapitulate the apelin receptor knockout mouse however this may be explained by the recent identification of a novel peptide, ELABELA/toddler/apela (ELA), identified in a previously designated non-coding region. We have previously demonstrated ELA expression localised to endothelial cells in human cardiovascular tissues and ELA binding to the human expressed apelin receptor. It remains to be determined whether the pharmacology of ELA is comparable to apelin and whether ELA is detectable in human plasma and, more importantly, whether ELA expression is altered in PAH where apelin expression is reduced.
Hypotheses: We hypothesised that ELA binds to the apelin receptor in human heart, activates both G protein-dependent and -independent signalling, is present in human plasma and is reduced in PAH.
Methods: Competition binding assays were performed in human heart. The potency (pD2) of ELA-32 and [Pyr1]apelin-13 was determined in cAMP, β-arrestin and internalisation assays in cells expressing the human apelin receptor. Levels of ELA and apelin were measured in human plasma samples. The presence and absence of ELA immunostaining was scored in pulmonary vessels (≤100μm diameter) in sections of human lung from PAH patients and controls (IRB approval) and compared using Fisher’s Exact Test.
Results: ELA-32 competed for binding of [125I][Pyr1]apelin-13 with an affinity of 0.21±0.06nM (n=3). Both ELA-32 and [Pyr1]apelin inhibited cAMP production (pD2=9.36±0.11, n=6; 9.61±0.12, n=5), elicited β-arrestin recruitment (9.13±0.18, n=16; 8.28±0.05, n=21) and receptor internalization (9.16±0.10, n=8; 8.55±0.07, n=7). ELA peptide was detectable in human plasma (0.49±0.05nM, n=25). The proportion of ELA-negative lung vessels was significantly increased in PAH (n=10) compared to controls (n=4) (p<0.01).
Conclusions: This study further characterizes ELA receptor pharmacology, signalling and plasma levels. We report for the first time down-regulation of ELA peptide in human disease. These findings support the apelin receptor as a target in the treatment of PAH.
Author Disclosures: P. Yang: None. J.J. Maguire: None. R.E. Kuc: None. M. Southwood: None. N.W. Morrell: None. A. Davenport: None.
- © 2015 by American Heart Association, Inc.