Corticotropin releasing hormone receptor 2 antagonist, RQ-00490721, for the prevention of pressure overload-induced cardiac dysfunction.
Cardiac hypertrophy
Corticotropin releasing hormone receptor 2 (CRHR2)
Drug discovery
G protein‐coupled receptor (GPCR)
Heart failure
cAMP-response element‐binding protein (CREB)
Journal
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
ISSN: 1950-6007
Titre abrégé: Biomed Pharmacother
Pays: France
ID NLM: 8213295
Informations de publication
Date de publication:
Feb 2022
Feb 2022
Historique:
received:
06
09
2021
revised:
14
12
2021
accepted:
19
12
2021
pubmed:
27
12
2021
medline:
22
3
2022
entrez:
26
12
2021
Statut:
ppublish
Résumé
G protein-coupled receptors (GPCRs) regulate the pathological and physiological functions of the heart. GPCR antagonists are widely used in the treatment of chronic heart failure. Despite therapeutic advances in the treatments for cardiovascular diseases, heart failure is a major clinical health problem, with significant mortality and morbidity. Corticotropin releasing hormone receptor 2 (CRHR2) is highly expressed in cardiomyocytes, and cardiomyocyte-specific deletion of the genes encoding CRHR2 suppresses pressure overload-induced cardiac dysfunction. This suggests that the negative modulation of CRHR2 may prevent the progression of heart failure. However, there are no systemic drugs against CRHR2. We developed a novel, oral, small molecule antagonist of CRHR2, RQ-00490721, to investigate the inhibition of CRHR2 as a potential therapeutic approach for the treatment of heart failure. In vitro, RQ-00490721 decreased CRHR2 agonist-induced 3', 5'-cyclic adenosine monophosphate (cAMP) production. In vivo, RQ-00490721 showed sufficient oral absorption and better distribution to peripheral organs than to the central nervous system. Oral administration of RQ-00490721 inhibited the CRHR2 agonist-induced phosphorylation of cAMP-response element binding protein (CREB) in the heart, which regulates a transcription activator involved in heart failure. RQ-00490721 administration was not found to affect basal heart function in mice but protected them from pressure overload-induced cardiac dysfunction. Our results suggest that RQ-00490721 is a promising agent for use in the treatment of chronic heart failure.
Sections du résumé
BACKGROUND
BACKGROUND
G protein-coupled receptors (GPCRs) regulate the pathological and physiological functions of the heart. GPCR antagonists are widely used in the treatment of chronic heart failure. Despite therapeutic advances in the treatments for cardiovascular diseases, heart failure is a major clinical health problem, with significant mortality and morbidity. Corticotropin releasing hormone receptor 2 (CRHR2) is highly expressed in cardiomyocytes, and cardiomyocyte-specific deletion of the genes encoding CRHR2 suppresses pressure overload-induced cardiac dysfunction. This suggests that the negative modulation of CRHR2 may prevent the progression of heart failure. However, there are no systemic drugs against CRHR2.
FINDINGS
RESULTS
We developed a novel, oral, small molecule antagonist of CRHR2, RQ-00490721, to investigate the inhibition of CRHR2 as a potential therapeutic approach for the treatment of heart failure. In vitro, RQ-00490721 decreased CRHR2 agonist-induced 3', 5'-cyclic adenosine monophosphate (cAMP) production. In vivo, RQ-00490721 showed sufficient oral absorption and better distribution to peripheral organs than to the central nervous system. Oral administration of RQ-00490721 inhibited the CRHR2 agonist-induced phosphorylation of cAMP-response element binding protein (CREB) in the heart, which regulates a transcription activator involved in heart failure. RQ-00490721 administration was not found to affect basal heart function in mice but protected them from pressure overload-induced cardiac dysfunction.
INTERPRETATION
CONCLUSIONS
Our results suggest that RQ-00490721 is a promising agent for use in the treatment of chronic heart failure.
Identifiants
pubmed: 34954642
pii: S0753-3322(21)01353-6
doi: 10.1016/j.biopha.2021.112566
pii:
doi:
Substances chimiques
Receptors, Corticotropin-Releasing Hormone
0
Cyclic AMP
E0399OZS9N
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
112566Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.