title: Salvianolic acid A, a matrix metalloproteinase-9 inhibitor of Salvia miltiorrhiza, attenuates aortic aneurysm formation in apolipoprotein E-deficient mice.
abstract: 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.
authors.affiliation: 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.
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Shenyang Pharmaceutical University, Wenhua Road #103, Shenyang 110016, China.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Xu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Defang
authors.initials: D
authors.lastname: Li
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.affiliation: Shenyang Pharmaceutical University, Wenhua Road #103, Shenyang 110016, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Shenyang Pharmaceutical University, Wenhua Road #103, Shenyang 110016, China.
authors.forename: Fukang
authors.initials: F
authors.lastname: Teng
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Deng
authors.affiliation: East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Ma
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Shenyang Pharmaceutical University, Wenhua Road #103, Shenyang 110016, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Wanying
authors.initials: W
authors.lastname: Wu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: jiangbh@simm.ac.cn.
authors.forename: Baohong
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: daguo@simm.ac.cn.
authors.forename: Den
authors.initials: D
authors.lastname: Guo
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001014:Aortic Aneurysm / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D002109:Caffeic Acids / Q000737:chemistry / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D007773:Lactates / Q000737:chemistry / Q000627:therapeutic use*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects* / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D027561:Salvia miltiorrhiza / Q000737:chemistry*
chemical_list: D001057:Apolipoproteins E; D002109:Caffeic Acids; D007773:Lactates; D061965:Matrix Metalloproteinase Inhibitors; D000804:Angiotensin II; C066201:salvianolic acid A; D020780:Matrix Metalloproteinase 9
keywords: Aortic aneurysm; Danshen; Doxycycline; Matrix metalloproteinase; Salvia miltiorrhiza; Salvianolic acid A