An EP4 Receptor Agonist Inhibits Cardiac Fibrosis Through Activation of PKA Signaling in Hypertrophied Heart

作者：Wang Qi; Oka Toru^*; Yamagami Kiyoshi; Lee Jong Kook; Akazawa Hiroshi; Naito Atsuhiko T; Yasui Taku; Ishizu Takamaru; Nakaoka Yoshikazu; Sakata Yasushi; Komuro Issei

来源：International Heart Journal, 2017, 58(1): 107-114.

DOI：10.1536/ihj.16-200

• Cardiac fibroblasts
• EP4 agonist

Cardiac fibrosis is a pathological feature of myocardium of failing heart and plays causative roles in arrhythmia and cardiac dysfunction, but its regulatory mechanisms remain largely elusive. In this study, we investigated the effects of the novel EP4 receptor agonist ONO-0260164 on cardiac fibrosis in hypertrophied heart and explored the regulatory mechanisms in cardiac fibroblasts.
In a mouse model of cardiac hypertrophy generated by transverse aortic constriction (TAC), ONO-0260164 treatment significantly prevented systolic dysfunction and progression of myocardial fibrosis at 5 weeks after TAC. In cultured neonatal rat cardiac fibroblasts, transforming growth factor-beta 1 (TGF-beta 1) induced upregulation of collagen type I, alpha 1 (Colla1) and type 3, alpha 1 (Col3a1), which was inhibited by ONO-0260164 treatment. ONO-0260164 activated protein kinase A (PKA) in the presence of TGF-beta 1 in the cardiac fibroblasts. PKA activation suppressed an increase in collagen expression induced by TGF-beta 1, indicating the important inhibitory roles of PKA activation in TGF-beta 1-mediated collagen induction.
We have demonstrated for the first time the antifibrotic effects of the novel EP4 agonist ONO-0260164 in vivo and in vitro, and the important role of PKA activation in the effects.

• 出版日期2017-1