Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima-city, Tokushima 770-8503, Japan.
Eur J Pharmacol. 2013 Jan 15;699(1-3):81-7. doi: 10.1016/j.ejphar.2012.11.045. Epub 2012 Dec 5.
Injury to the heart can result in cardiomyocyte hypertrophy, fibrosis, and cell death. Myocarditis sometimes progresses to dilated cardiomyopathy. We previously reported that ONO-1301, a synthetic prostacyclin agonist with thromboxane-synthase inhibitory activity, promotes production of hepatocyte growth factor (HGF) from various cell types and ameliorates ischemia-induced left ventricle dysfunction in the mouse, rat and pig. Here, we investigated the therapeutic efficacy of ONO-1301 in a rat model of myosin-induced experimental autoimmune myocarditis, in which the heart transits from an acute inflammatory phase to a chronic dilated cardiomyopathy phase. Four weeks after myosin injection to Lewis rats, ONO-1301 (6 mg/kg/day) was orally administered for 4 weeks (ONO-1301 group). Hemodynamic parameters and plasma brain natriuretic peptide (BNP) level were significantly improved by ONO-1301. Histological analysis revealed that capillary density in the myocardium was significantly increased by ONO-1301. ONO-1301 increased circulating endothelial progenitor cells (EPC) as determined by FACS analysis. These beneficial effects of ONO-1301 were partially abrogated by a neutralizing anti-HGF antibody (8 mg/kg/dose). These findings indicate beneficial effects of ONO-1301 in a rat experimental autoimmune myocarditis model.
心肌损伤可导致心肌细胞肥大、纤维化和细胞死亡。心肌炎有时会进展为扩张型心肌病。我们之前曾报道，具有血栓素合酶抑制活性的合成前列环素激动剂 ONO-1301 可促进各种细胞类型产生肝细胞生长因子 (HGF)，并改善小鼠、大鼠和猪的缺血性左心室功能障碍。在这里，我们研究了 ONO-1301 在肌球蛋白诱导的实验性自身免疫性心肌炎大鼠模型中的治疗效果，在该模型中，心脏从急性炎症期过渡到慢性扩张型心肌病期。在向 Lewis 大鼠注射肌球蛋白 4 周后，ONO-1301（6mg/kg/天）口服给药 4 周（ONO-1301 组）。ONO-1301 显著改善了血流动力学参数和血浆脑钠肽 (BNP) 水平。组织学分析显示，ONO-1301 显著增加了心肌中的毛细血管密度。ONO-1301 通过 FACS 分析增加了循环内皮祖细胞 (EPC)。抗 HGF 中和抗体（8mg/kg/剂量）部分阻断了 ONO-1301 的这些有益作用。这些发现表明 ONO-1301 在大鼠实验性自身免疫性心肌炎模型中具有有益作用。
