Zhang Tingting, Xu Jinghua, Li Defang, Chen Jing, Shen Xu, Xu Feng, Teng Fukang, Deng Yanping, Ma Hongmei, Zhang Li, Zhang Ge, Zhang Zhou, Wu Wanying, Liu Xuan, Yang Min, Jiang Baohong, Guo Den
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Shenyang Pharmaceutical University, Wenhua Road #103, Shenyang 110016, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Shenyang Pharmaceutical University, Wenhua Road #103, Shenyang 110016, China.
Phytomedicine. 2014 Sep 15;21(10):1137-45. doi: 10.1016/j.phymed.2014.05.003. Epub 2014 Jun 7.
Aortic aneurysm (AA) is a life-threatening vascular disease in defect of effective pharmaceutical therapy. Matrix metalloproteinase-9 (MMP-9) is implicated in the development of chronic vascular diseases including aneurysm, but the effective MMP-9 inhibitors are far from development. To develop new candidate for AA therapy, we evaluated the efficiency of salvianolic acid A (SalA), a novel MMP-9 inhibitor, on AA progression in a mouse model and characterized the mechanism of action. SalA is a water soluble compound of the herbal drug Rhizoma Salviae miltiorrhizae (Danshen) which in China is widely used for the treatment of hypertension, coronary artery diseases and myocardial infarction. MMPs activity was evaluated by enzyme kinetic analysis in vitro and in-gel gelatin zymography in vivo. SalA showed selectivity on gelatinase (MMP-2 and MMP-9) than on collagenase (MMP-8 and MMP-13) in vitro, and specificity on MMP-9 than MMP-2 in vivo. Aortic aneurysm was induced by angiotension II (AngII) in apolipoprotein E-deficient (ApoE(-/-)) mice. Aortic structure was evaluated by hematoxylin and eosin, picrosirius red, orein stain. Macrophage infiltration was detected by immunohistochemistry in vivo and transwell in vitro. Comparing with doxycycline (Dox), a well-known MMPs inhibitor, SalA showed similar efficiency against AA progression. SalA significantly decreased aortic diameter and aneurysm severity, ameliorated integrity of vascular structure, inhibited elastin fragmentation and macrophage infiltration. Furthermore, SalA showed greater safety than Dox based on hepatotoxicity evaluation. Our results demonstrated that SalA held great potential for AA therapy.
主动脉瘤（AA）是一种缺乏有效药物治疗的危及生命的血管疾病。基质金属蛋白酶-9（MMP-9）与包括动脉瘤在内的慢性血管疾病的发展有关，但有效的MMP-9抑制剂远未开发出来。为了开发治疗AA的新候选药物，我们评估了新型MMP-9抑制剂丹酚酸A（SalA）对小鼠模型中AA进展的疗效，并对其作用机制进行了表征。SalA是中药丹参的一种水溶性化合物，在中国广泛用于治疗高血压、冠状动脉疾病和心肌梗死。通过体外酶动力学分析和体内凝胶明胶酶谱法评估MMPs活性。SalA在体外对明胶酶（MMP-2和MMP-9）的选择性高于对胶原酶（MMP-8和MMP-13）的选择性，在体内对MMP-9的特异性高于MMP-2。用血管紧张素II（AngII）在载脂蛋白E缺陷（ApoE(-/-)）小鼠中诱导主动脉瘤。通过苏木精和伊红、天狼星红、奥瑞因染色评估主动脉结构。通过体内免疫组织化学和体外transwell检测巨噬细胞浸润。与著名的MMPs抑制剂强力霉素（Dox）相比，SalA对AA进展显示出相似的疗效。SalA显著降低主动脉直径和动脉瘤严重程度，改善血管结构完整性，抑制弹性蛋白断裂和巨噬细胞浸润。此外，基于肝毒性评估，SalA显示出比Dox更高的安全性。我们的结果表明，SalA在AA治疗方面具有巨大潜力。
