Sanada Fumihiro, Kanbara Yasuhiro, Taniyama Yoshiaki, Otsu Rei, Carracedo Miguel, Ikeda-Iwabu Yuka, Muratsu Jun, Sugimoto Ken, Yamamoto Koichi, Rakugi Hiromi, Morishita Ryuichi
From the Departments of Clinical Gene Therapy (F.S., Y.K., Y.T., R.O., M.C., Y.I.-I., J.M., R.M.) and Geriatric and General Medicine (Y.T., J.M., K.S., K.Y., H.R.), Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Arterioscler Thromb Vasc Biol. 2016 Mar;36(3):545-52. doi: 10.1161/ATVBAHA.115.307011. Epub 2016 Jan 14.
Peripheral arterial disease is highly prevalent in the elderly and in the subjects with cardiovascular risk factors such as diabetes. Approximately 2% to 4% of those affected with peripheral arterial disease commonly complain of intermittent claudication. Cilostazol, a type III phosphodiesterase inhibitor, is the only Food and Drug Administration-approved drug for the treatment of intermittent claudication. Cilostazol has been shown to be beneficial for the improvement of pain-free walking distance in patients with intermittent claudication in a series of randomized clinical trials. However, the underlying mechanism how cilostazol improved intermittent claudication symptoms is still unclear.
In this study, the effect of cilostazol on ischemic leg was investigated in mouse ischemic hindlimb model. Administration of cilostazol significantly increased the expression of hepatocyte growth factor (HGF), vascular endothelial growth factor, angiopoietin-1, and peroxisome proliferator-activated receptor-γ in vasculature. The capillary density in ischemic leg was also significantly increased in cilostazol treatment group when compared with control and aspirin treatment group. However, an increase in capillary density and the expression of growth factors was almost completely abolished by coadministration of HGF-neutralizing antibody, suggesting that cilostazol enhanced angiogenesis mainly through HGF. In vitro experiment revealed that cilostazol treatment increased HGF production in vascular smooth muscle cells via 2 major pathways: peroxisome proliferator-activated receptor-γ and cAMP pathways.
Our data suggest that the favorable effects of cilostazol on ischemic leg might be through the angiogenesis through the induction of HGF via peroxisome proliferator-activated receptor-γ and cAMP pathways.
外周动脉疾病在老年人以及患有糖尿病等心血管危险因素的人群中极为普遍。约2%至4%的外周动脉疾病患者通常会抱怨间歇性跛行。西洛他唑，一种III型磷酸二酯酶抑制剂，是唯一被美国食品药品监督管理局批准用于治疗间歇性跛行的药物。在一系列随机临床试验中，西洛他唑已被证明对改善间歇性跛行患者的无痛步行距离有益。然而，西洛他唑改善间歇性跛行症状的潜在机制仍不清楚。
在本研究中，在小鼠缺血后肢模型中研究了西洛他唑对缺血腿部的影响。给予西洛他唑显著增加了血管中肝细胞生长因子（HGF）、血管内皮生长因子、血管生成素-1和过氧化物酶体增殖物激活受体-γ的表达。与对照组和阿司匹林治疗组相比，西洛他唑治疗组缺血腿部的毛细血管密度也显著增加。然而，同时给予HGF中和抗体几乎完全消除了毛细血管密度和生长因子表达的增加，这表明西洛他唑主要通过HGF促进血管生成。体外实验表明，西洛他唑治疗通过两条主要途径增加血管平滑肌细胞中HGF的产生：过氧化物酶体增殖物激活受体-γ和cAMP途径。
我们的数据表明，西洛他唑对缺血腿部的有益作用可能是通过过氧化物酶体增殖物激活受体-γ和cAMP途径诱导HGF从而促进血管生成实现的。
