A Novel Long-Acting Prostacyclin Agonist (ONO-1301) With an Angiogenic Effect: Promoting Synthesis of Hepatocyte Growth Factor and Increasing Cyclic AMP Concentration via IP-Receptor Signaling

Abstract

The purpose of this study was to evaluate the angiogenic potency of ONO-1301, a novel prostacyclin agonist, using a murine sponge model. Solutions of ONO-1301 or hepatocyte growth factor (HGF), as a positive control, were injected into sponges in the backs of mice, daily for 14 days. Hemoglobin and HGF levels in the sponge were increased for up to 14 days on daily treatment with ONO-1301 while on HGF treatment, they peaked on day 7 and had decreased again by day 14. ONO-1301 also upregulated c-Met expression for 14 days in a dose-dependent manner. When the mice were pretreated with an antibody to HGF or the prostaglandin I (IP)-receptor antagonist CAY10441, the angiogenic effect of ONO-1301 was dramatically reduced. Plasma concentrations of cyclic adenosine monophosphate (cAMP) were increased in a dose-dependent manner by once daily treatment with ONO-1301 for 14 days. This effect was reduced by pretreatment with the IP-receptor antagonist. In conclusion, hemoglobin level was increased by repeated treatment with ONO-1301 for 14 days. It is suggested that ONO-1301 induced angiogenesis by promoting the synthesis of HGF and upregulated c-Met expression, followed by an increase in cAMP concentrations mediated by IP-receptor signaling. Keywords:: ONO-1301, hepatocyte growth factor (HGF), angiogenesis, sponge model, hemoglobin