Salvianolic acid A, a matrix metalloproteinase-9 inhibitor of Salvia miltiorrhiza, attenuates aortic aneurysm formation in apolipoprotein E-deficient mice

• Published in: Phytomedicine (Stuttgart) 2014-09, Vol.21 (10), p.1137-1145
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Angiotensin II - adverse effects; Animals; Aorta - drug effects; Aorta - pathology; Aortic aneurysm; Aortic Aneurysm - chemically induced; Aortic Aneurysm - drug therapy; Aortic Aneurysm - pathology; Aortic aneurysms; Apolipoproteins E - genetics; Caffeic Acids - chemistry; Caffeic Acids - therapeutic use; Care and treatment; Cell Line, Tumor; Cell Movement - drug effects; Cell Survival - drug effects; Danshen; Disease Models, Animal; Doxycycline; Enzyme inhibitors; Health aspects; Lactates - chemistry; Lactates - therapeutic use; Male; Matrix metalloproteinase; Matrix Metalloproteinase 9 - drug effects; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinase Inhibitors - chemistry; Matrix Metalloproteinase Inhibitors - therapeutic use; Mice; Mice, Inbred C57BL; Mice, Knockout; Sage; Salvia miltiorrhiza; Salvia miltiorrhiza - chemistry; Salvianolic acid A; Testing
• ISSN: 0944-7113; 1618-095X
• DOI: 10.1016/j.phymed.2014.05.003

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.