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[PMID]: | 28137936 |
[Au] Autor: | Yang P; Read C; Kuc RE; Buonincontri G; Southwood M; Torella R; Upton PD; Crosby A; Sawiak SJ; Carpenter TA; Glen RC; Morrell NW; Maguire JJ; Davenport AP |
[Ad] Endereço: | From Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, UK (P.Y., C.R., R.E.K., J.J.M., A.P.D.); Wolfson Brain Imaging Centre, Department of Clinical Neuroscience, University of Cambridge, UK (G.B., S.J.S., T.A.C.); Depar |
[Ti] Título: | 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. |
[So] Source: | Circulation;135(12):1160-1173, 2017 Mar 21. | [Is] ISSN: | 1524-4539 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | 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 downregulated, and to demonstrate attenuation of PAH severity with exogenous administration of ELA in a rat model. METHODS: docking analysis, competition binding experiments, and downstream 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 real-time quantitative polymerase chain reaction, dual-labeling immunofluorescent staining, and immunoassays. Acute cardiac effects of ELA-32 and [Pyr ]apelin-13 were assessed by MRI and cardiac catheterization in anesthetized rats. Cardiopulmonary human and rat tissues from PAH patients and monocrotaline- 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 monocrotaline rat model. RESULTS: ELA competed for binding of apelin in human heart with overlap for the 2 peptides indicated by modeling. ELA activated G-protein- and ß-arrestin-dependent pathways. We detected ELA expression in human vascular endothelium and plasma. Comparable to apelin, ELA increased cardiac contractility, ejection fraction, and 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 remodeling in monocrotaline-exposed rats. CONCLUSIONS: These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin, and is downregulated in human disease and rodent PAH models, and exogenous peptide can reduce the severity of cardiopulmonary remodeling and function in PAH in rats. This study provides additional proof of principle that an apelin receptor agonist may be of therapeutic use in PAH in humans. |
[Mh] Termos MeSH primário: |
Hipertensão Pulmonar/tratamento farmacológico Hormônios Peptídicos/uso terapêutico
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[Mh] Termos MeSH secundário: |
Sequência de Aminoácidos Animais Apelina Sítios de Ligação Cateterismo Modelos Animais de Doenças Regulação para Baixo/efeitos dos fármacos Endotélio Vascular/efeitos dos fármacos Endotélio Vascular/metabolismo Ventrículos do Coração/efeitos dos fármacos Ventrículos do Coração/metabolismo Seres Humanos Hipertensão Pulmonar/fisiopatologia Peptídeos e Proteínas de Sinalização Intercelular/agonistas Peptídeos e Proteínas de Sinalização Intercelular/química Peptídeos e Proteínas de Sinalização Intercelular/metabolismo Peptídeos e Proteínas de Sinalização Intercelular/farmacologia Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico Masculino Simulação de Dinâmica Molecular Hormônios Peptídicos/química Hormônios Peptídicos/metabolismo Hormônios Peptídicos/farmacologia Estrutura Terciária de Proteína Ratos Ratos Sprague-Dawley
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[Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (APLN protein, human); 0 (Apelin); 0 (ELA peptide, human); 0 (Intercellular Signaling Peptides and Proteins); 0 (Peptide Hormones); 0 (apelin-13 peptide) |
[Em] Mês de entrada: | 1705 |
[Cu] Atualização por classe: | 171116 |
[Lr] Data última revisão:
| 171116 |
[Sb] Subgrupo de revista: | AIM; IM |
[Da] Data de entrada para processamento: | 170201 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1161/CIRCULATIONAHA.116.023218 |
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