The urotensin II receptor antagonist DS37001789 ameliorates mortality in pressure-overload mice with heart failure

Abstract This study was designed to evaluate the effects of DS37001789, a novel and highly potent urotensin II (U-II) receptor (GPR14) antagonist, against mortality, hypertrophy, and cardiac dysfunction in pressure-overload hypertrophy by transverse aortic constriction (TAC) in mice. In addition, we analyzed the phenotype of GPR14 knockout (KO) mice after TAC induction to confirm the contribution of the U-II/GPR14 system. The oral administration of 0.2% DS37001789 to TAC mice for 12 weeks significantly ameliorated the mortality rate and 0.2% DS37001789 for 4 weeks significantly improved cardiac function by pressure-volume analysis. GPR14 expression was significantly upregulated in the left ventricle in the TAC mice treated with 0.2% DS37001789. Moreover, we confirmed that the significant amelioration of mortality was accomplished by the inhibition of cardiac enlargement and the improvement of cardiac function in GPR14 KO mice after TAC surgery. These results suggest that the U-II/GPR14 system contributes to the progression of heart failure and its blockade ameliorates the mortality via improved cardiac function. The U-II/GPR14 system may thus be an attractive target for treating heart failure with pathological cardiac hypertrophy and DS37001789 may be a novel therapeutic agent for heart failure in patients with pressure-overload conditions such as hypertension and aortic valve stenosis.