Abstract 11765: An Orally Available Novel Antagonist Against Corticotropin Releasing Hormone Receptor 2 Prevents Cardiac Dysfunction in Mouse Heart Failure Model

• Published in: Circulation (New York, N.Y.) Vol. 140; no. Suppl_1 Suppl 1; p. A11765
• Main Authors: Takefuji, Mikito, Park, Hyi-Man, Tsuchihira, Ayako, Ohmi, Masashi, Fujiuchi, Akiyoshi, Isogai, Yumi, Murohara, Toyoaki
• Format: Journal Article
• Language: English
• Published: by the American College of Cardiology Foundation and the American Heart Association, Inc 19.11.2019
• DOI: 10.1161/circ.140.suppl_1.11765
• ISSN: 0009-7322

IntroductionIn the heart, G protein-coupled receptors (GPCRs) regulate cardiac function in response to extracellular stimuli and play a pivotal role in cardiac dysfunction. GPCR antagonists are widely used to treat patients with heart failure. Although the heart expresses several GPCRs, only β adrenergic and angiotensin II receptors antagonists are clinically used as a long-term treatment for patients with chronic heart failure. Despite these available therapies, mortality and hospitalization rates have remained relatively high, suggesting that additional uncharacterized GPCRs may also mediate disease pathophysiology. We have shown that corticotropin releasing hormone receptor 2 (Crhr2) is a GPCR highly expressed in cardiomyocytes and continuous infusion of urocortin 2, an endogenous Crhr2 agonist, reduced left ventricular (LV) ejection fraction in mice, suggesting that constitutive Crhr2 activation causes cardiac dysfunction.HypothesisAn orally available Crhr2 antagonist is a promising therapy for chronic heart failure.MethodsA novel small molecule Crhr2 antagonist RQ-00490721, which was identified in our research, was usded for this study. In vivo efficacy was evaluated using transverse aortic constriction (TAC) model in mice. RQ-00490721 was orally administered twice a day for 4 weeks after the TAC surgery, and cardiac function was assessed by echocardiography.ResultsIn control, TAC resulted in a significant increase in cardiac hypertrophy as determined by postmortem analysis of the ratio of LV weight to body weight, whereas oral treatment of RQ-00490721 protected mice from pressure-overload-induced cardiac hypertrophy. Furthermore, RQ-00490721 prevented mice from TAC-induced decrease of the LV fractional shortening as determined by echocardiography. The treatment decreased maladaptive cAMP-dependent signaling such as phosphorylation of cAMP response element binding protein.ConclusionsOur data show that intervention by a Crhr2 antagonist prevents pressure overload-induced cardiac hypertrophy and dysfunction in mouse heart failure model and suggests that Crhr2 blockade is a promising therapeutic strategy for patients with chronic heart failure.