A synthetic prostacyclin agonist with thromboxane synthase inhibitory activity, ONO-1301, protects myocardium from ischemia/reperfusion injury

Abstract

ONO-1301, a synthetic prostacyclin agonist with thromboxane synthase inhibitory activity, promotes the production of hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) by various cell types. Here, we evaluated the therapeutic efficacy of ONO-1301 in rats with ischemia/reperfusion injury. Ligation of the left anterior descending arteries was performed in 10-week-old Wistar rats, and released 30 min later. A slow-release form of ONO-1301 was administered subcutaneously at 3 h and 3 weeks after reperfusion injury. Hemodynamic parameters were significantly improved in the ONO-1301 group. Histological analysis revealed that ONO-1301 suppressed ischemic and fibrotic changes in the myocardium (ischemic area, control group: 58.6 ± 8.7% vs. ONO-1301 group: 44.4 ± 5.8%, fibrotic area, 33.5 ± 5.9% vs. 22.3 ± 6.2%, P < 0.05, respectively), and enhanced neovascularization in the border zone. HGF expression was up-regulated by ONO-1301. Double-immunostaining revealed that myofibroblasts in the border zone of ischemic myocardium mainly expressed HGF. Our findings suggest that ONO-1301 might have therapeutic potential in treating ischemic heart disease.

Introduction

Ischemic heart disease is predicted to be the leading cause of death in developed countries in the near future (Lopez and Murray, 1998). Although treatment for ischemic heart disease such as revascularization therapy has progressed, it has been established that part of the cell death caused by transient coronary occlusion occurs at the time of reperfusion. The last two decades have witnessed major advances in understanding the mechanism of reperfusion injury, and this progress has allowed the use of different experimental strategies to decrease reperfusion injury (Garcia-Dorado et al., 2009). However, the clinical applicability of these potential therapies has been generally very limited because of the absence of specific drugs suitable for human use.

Prostaglandin (PG) I₂, which is also called prostacyclin, and its analogues have been reported to attenuate cardiac reperfusion injury in vivo (Aitchison and Coker, 1999, Cargnoni et al., 1991, Zacharowski et al., 1999). Xiao et al. (2001) reported the protective effect of the PGI₂ receptor. The mechanism of protection was proposed to be a result of inhibitory effects on platelets (Aherne et al., 1986) and neutrophils (Simpson et al., 1987). However, many aspects of these mechanisms remain to be elucidated.

ONO-1301, (E)-[5-[2-[1-phenyl-1-(3-pyridyl)methylideneaminooxy]ethyl]-7,8-dihydronaphthalen-1-yloxy]acetic acid, is a synthetic prostacyclin agonist lacking the typical prostanoid structures, including a five-membered ring and allylic alcohol (Hayashi et al., 1997, Imawaka and Sugiyama, 1998, Murakami et al., 2006, Rudd et al., 2000). ONO-1301 shows remarkable chemical and biological stability because it lacks a prostanoid structure. Moreover, because of the presence of a 3-pyridine radical, ONO-1301 inhibits thromboxane synthase activity through interaction with carboxylic acid via a hydrogen bond (Hayashi et al., 1997, Kataoka et al., 2005, Murakami et al., 2006). We previously reported that local administration of a slow-release form of ONO-1301 into murine ischemic heart was effective to prevent left ventricular remodeling and improve the survival rate (Nakamura et al., 2007). We also reported that local delivery of ONO-1301 augmented collateral growth and improved cardiac function in a swine cardiac ischemia model (Iwata et al., 2009). The beneficial effect of ONO-1301 in the treatment of cardiac ischemia was partly mediated by up-regulation of angiogenic molecules, including HGF and VEGF, via a cAMP-mediated pathway (Nakamura et al., 2007). Since small molecules could be administered repetitively without invasive procedures such as bone marrow aspiration for cell therapy, it could be an attractive strategy to stimulate local residual cells with small synthetic molecules to produce proangiogenic factors.

Here, we investigated the therapeutic efficacy of a slow-release form of ONO-1301 in rats with cardiac reperfusion injury. Our findings suggested that ONO-1301 might be effective in the treatment of patients with ischemic heart disease.