Heart failure inhibitor

+ See all authors and affiliations

Sci. Signal.  11 Jul 2017:
Vol. 10, Issue 487, eaao3132
DOI: 10.1126/scisignal.aao3132

Targeting a G protein–coupled receptor in cardiomyocytes offers protection in a mouse model of cardiac failure.

Although treatments for many cardiovascular diseases continue to improve, patients with heart failure still have a poor prognosis. To identify factors that contribute to heart failure, Tsuda et al. performed transcriptomic analysis of genes encoding G protein–coupled receptors (GPCRs) in cardiomyocytes isolated from mice two weeks after they were subjected to transverse aortic constriction (TAC). Crhr2 mRNA, which encodes corticotropin releasing hormone receptor 2 (Crhr2), was the most abundant mRNA in these cells and also showed the greatest increase in response to TAC. Mice subjected to TAC also exhibited increases in the serum concentration of the Crhr2 agonist urocortin2 (Ucn2). Control mice continuously administered Ucn2 for four weeks developed cardiac hypertrophy and dysfunction. These effects were not seen in mice with tamoxifen-inducible, cardiomyocyte-specific deletion of Crhr2 (cmc-Crhr2-KO mice). Treatment of control mice with the Crhr2 antagonist antisauvagine-30 one week after undergoing TAC protected them from cardiac dysfunction. Reporter assays showed that Crhr2 stimulation led to activation of Gαs G proteins and increased production of cyclic adenosine monophosphate (cAMP), a second messenger whose accumulation is associated with cardiotoxicity. Western blotting analysis of cardiomyocytes showed that antisauvagine-30 inhibited the TAC-induced accumulation of cAMP and activation of downstream signaling pathways. Compared with healthy patients, patients with nonischemic dilated cardiomyopathy had more than seven-fold greater serum concentrations of Ucn2. Together, these data suggest that Crhr2 antagonists should be investigated as a potential therapy for the treatment of patients with chronic heart failure.

Highlighted Article

View Abstract

Navigate This Article