Salvianolic acid B functioned as a competitive inhibitor of matrix metalloproteinase-9 and efficiently prevented cardiac remodeling.
BACKGROUND
Infarct-induced left ventricular (LV) remodeling is a deleterious consequence after acute myocardial infarction (MI) which may further advance to congestive heart failure. Therefore, new therapeutic strategies to attenuate the effects of LV remodeling are urgently needed. Salvianolic acid B (SalB) from Salviae mitiorrhizae, which has been widely used in China for the treatment of cardiovascular diseases, is a potential candidate for therapeutic intervention of LV remodeling targeting matrix metalloproteinase-9 (MMP-9).


RESULTS
Molecular modeling and LIGPLOT analysis revealed in silico docking of SalB at the catalytic site of MMP-9. Following this lead, we expressed truncated MMP-9 which contains only the catalytic domain, and used this active protein for in-gel gelatin zymography, enzymatic analysis, and SalB binding by Biacore. Data generated from these assays indicated that SalB functioned as a competitive inhibitor of MMP-9. In our rat model for cardiac remodeling, western blot, echocardiography, hemodynamic measurement and histopathological detection were used to detect the effects and mechanism of SalB on cardio-protection. Our results showed that in MI rat, SalB selectively inhibited MMP-9 activities without affecting MMP-9 expression while no effect of SalB was seen on MMP-2. Moreover, SalB treatment in MI rat could efficiently increase left ventricle wall thickness, improve heart contractility, and decrease heart fibrosis.


CONCLUSIONS
As a competitive inhibitor of MMP-9, SalB presents significant effects on preventing LV structural damage and preserving cardiac function. Further studies to develop SalB and its analogues for their potential for cardioprotection in clinic are warranted.
Jiang
Baohong
B
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Chen
Jing
J
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Xu
Lingling
L
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Gao
Zhenting
Z
School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
Deng
Yanping
Y
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Wang
Yanhui
Y
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|Shenyang Pharmaceutical University, Wenhua Road #103, Shenyang 110016, China.
Xu
Feng
F
Shenyang Pharmaceutical University, Wenhua Road #103, Shenyang 110016, China.
Shen
Xu
X
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Guo
De-An
DA
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
D000818:Animals; D001572:Benzofurans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D001665:Binding Sites; D003198:Computer Simulation; D015536:Down-Regulation / Q000187:drug effects; D015195:Drug Design; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005355:Fibrosis; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008968:Molecular Conformation; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects*; D053630:Depsides
D001572:Benzofurans; D004365:Drugs, Chinese Herbal; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011993:Recombinant Fusion Proteins; C076944:salvianolic acid B; D053630:Depsides; C522363:Mmp2 protein, rat