Key result
Oral CRHR2 antagonist RQ-00490721 protects against pressure overload-induced cardiac dysfunction without altering basal heart function.
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Demonstrates that oral CRHR2 antagonist RQ-00490721 prevents pressure overload-induced cardiac dysfunction in mice, suggesting a novel heart failure therapy.
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: 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: Our results suggest that RQ-00490721 is a promising agent for use in the treatment of chronic heart failure.
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Mori et al. (2021) studied Pressure overload-induced cardiac dysfunction / Chronic heart failure. RQ-00490721 (oral CRHR2 antagonist) was evaluated on Prevention of pressure overload-induced cardiac dysfunction and inhibition of CRHR2-mediated cAMP/CREB signaling. Oral CRHR2 antagonist RQ-00490721 inhibited cardiac CREB phosphorylation and protected mice from pressure overload-induced cardiac dysfunction without affecting basal heart function.
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