Peng Wu1, Na Han2, Haitao Yu3, Linlin Wang3, Xue Li3, Zhihui Dong4, Weiguo Fu4, Hoichi Yorinaka5, Kenka Cho6, Wanying Wu3, Xuan Liu3, Min Yang3, De-An Guo3, Jun Yin7, Baohong Jiang8. 1. 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. 2. Shenyang Pharmaceutical University, Wenhua Road #103, Shenyang 110016, China. 3. State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. 4. Departments of Vascular Surgery, Zhongshan Hospital, Fudan University, China. 5. Department of Pharmacology and Molecular Therapeutics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Japan. 6. Takarazuka University of Medical and Health Care, Hanayashiki-Midorigaoka, Takarazuka City 6660162, Japan. 7. Shenyang Pharmaceutical University, Wenhua Road #103, Shenyang 110016, China. Electronic address: yinjun826@sina.com. 8. State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: jiangbh@simm.ac.cn.
Abstract
AIMS: Aortic aneurysm is a disastrous vascular disease with high morbidity and mortality. Matrix metalloproteinases (MMPs), especially MMP-9, is implicated in the development of aortic aneurysm, but the effective MMP inhibitors are far from development. To develop new candidate compound for aortic aneurysm therapy, we evaluated the effects of salvianolic acid C (SalC) against the formation of aortic aneurysm. MATERIALS AND METHODS: Aortic aneurysm was induced by implantation of angiotension II (AngII) minipump in apolipoprotein E-deficient (ApoE-/-) mice. MMPs activity was evaluated by enzyme kinetic analysis in vitro and in-gel gelatin zymography in vivo. The formation of aortic aneurysm was confirmed based on aortic maximum diameter. Hematoxylin and eosin stain was used to evaluate aortic structure, picrosirius red stain was for collagen deposition, and orcein stain was for elastin fragmentation. Macrophage infiltration was detected by CD68 immunohistochemistry. KEY FINDINGS: Firstly, SalC showed significant inhibition on the activity of MMP-2 and MMP-9. Aortic aneurysm was defined as >50% increase in maximum diameter of aorta, and the down-regulated tendency of 20mg/kg SalC against formation of aortic aneurysm was detected. Also, 22.2% rupture was detected in ApoE-/- mice, while no rupture of aortic aneurysm was found with 20mg/kg SalC treatment. Then, SalC was detected to maintain the integrity of aortic structure and protect elastin against fragmentation. Finally, SalC considerably inhibited infiltration of macrophage in the injury site of aorta. SIGNIFICANCE: SalC significantly ameliorated the progression of aortic aneurysm in ApoE-/- mice, and held great potential for aortic aneurysm therapy.
AIMS: Aortic aneurysm is a disastrous vascular disease with high morbidity and mortality. Matrix metalloproteinases (MMPs), especially MMP-9, is implicated in the development of aortic aneurysm, but the effective MMP inhibitors are far from development. To develop new candidate compound for aortic aneurysm therapy, we evaluated the effects of salvianolic acid C (SalC) against the formation of aortic aneurysm. MATERIALS AND METHODS:Aortic aneurysm was induced by implantation of angiotension II (AngII) minipump in apolipoprotein E-deficient (ApoE-/-) mice. MMPs activity was evaluated by enzyme kinetic analysis in vitro and in-gel gelatin zymography in vivo. The formation of aortic aneurysm was confirmed based on aortic maximum diameter. Hematoxylin and eosin stain was used to evaluate aortic structure, picrosirius red stain was for collagen deposition, and orcein stain was for elastin fragmentation. Macrophage infiltration was detected by CD68 immunohistochemistry. KEY FINDINGS: Firstly, SalC showed significant inhibition on the activity of MMP-2 and MMP-9. Aortic aneurysm was defined as >50% increase in maximum diameter of aorta, and the down-regulated tendency of 20mg/kg SalC against formation of aortic aneurysm was detected. Also, 22.2% rupture was detected in ApoE-/- mice, while no rupture of aortic aneurysm was found with 20mg/kg SalC treatment. Then, SalC was detected to maintain the integrity of aortic structure and protect elastin against fragmentation. Finally, SalC considerably inhibited infiltration of macrophage in the injury site of aorta. SIGNIFICANCE: SalC significantly ameliorated the progression of aortic aneurysm in ApoE-/- mice, and held great potential for aortic aneurysm therapy.