Journal
PHYTOMEDICINE
Volume 21, Issue 10, Pages 1137-1145Publisher
ELSEVIER GMBH
DOI: 10.1016/j.phymed.2014.05.003
Keywords
Salvianolic acid A; Salvia miltiorrhiza; Aortic aneurysm; Matrix metalloproteinase; Doxycycline; Danshen
Categories
Funding
- National Science & Technology Major Project for Key New Drug Creation and Manufacturing Program [2013ZX09103002-024, 2011ZX09307-002-03]
- National Natural Science Foundation of China Grants [81173587]
- Shanghai Science and Technology Development Foundation of Experimental Animal Research Project [12140902400]
- Global Research Network for Medicinal Plants (GRNMP) and King Saud University
- National High Technology Research and Development Program (863 Program) of China [SS2013AA09002]
- Twelfth Five-Year National Science & Technology Support Program [2012BAI29B06]
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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 (Ana) 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. (C) 2014 Elsevier GmbH. All rights reserved.
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