Nishi Mina, Tagawa Hideki, Ueno Masumi, Marumoto Shinji, Nagayama Takahiro
Specialty Medicine Research Laboratories II, Daiichi-Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Daiichi Sankyo Pharma Development, Daiichi-Sankyo, Inc., 211 Mt. Airy Road, Basking Ridge, NJ 07920, USA.
Heliyon. 2020 Feb 3;6(2):e03352. doi: 10.1016/j.heliyon.2020.e03352. eCollection 2020 Feb.
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.
本研究旨在评估新型强效尿紧张素II（U-II）受体（GPR14）拮抗剂DS37001789对小鼠经主动脉缩窄（TAC）诱导的压力超负荷肥大模型中死亡率、心肌肥大和心脏功能障碍的影响。此外，我们分析了TAC诱导后GPR14基因敲除（KO）小鼠的表型，以确认U-II/GPR14系统的作用。给TAC小鼠口服0.2% DS37001789，持续12周，可显著改善死亡率；口服0.2% DS37001789，持续4周，通过压力-容积分析可显著改善心脏功能。在用0.2% DS37001789治疗的TAC小鼠的左心室中，GPR14表达显著上调。此外，我们证实，TAC手术后，GPR14 KO小鼠通过抑制心脏扩大和改善心脏功能，显著改善了死亡率。这些结果表明，U-II/GPR14系统促进心力衰竭的进展，阻断该系统可通过改善心脏功能降低死亡率。因此，U-II/GPR14系统可能是治疗病理性心肌肥大所致心力衰竭的一个有吸引力的靶点，DS37001789可能是治疗高血压和主动脉瓣狭窄等压力超负荷情况下心力衰竭患者的新型治疗药物。
