title: Salvianolic acid A, a novel matrix metalloproteinase-9 inhibitor, prevents cardiac remodeling in spontaneously hypertensive rats.
abstract: Cardiac fibrosis is a deleterious consequence of hypertension which may further advance to heart failure and increased matrix metalloproteinase-9 (MMP-9) contributes to the underlying mechanism. Therefore, new therapeutic strategies to attenuate the effects of MMP-9 are urgently needed. In the present study, we characterize salvianolic acid A (SalA) as a novel MMP-9 inhibitor at molecular, cellular and animal level. We expressed a truncated form of MMP-9 which contains only the catalytic domain (MMP-9 CD), and used this active protein for enzymatic kinetic analysis and Biacore detection. Data generated from these assays indicated that SalA functioned as the strongest competitive inhibitor of MMP-9 among 7 phenolic acids from Salvia miltiorrhiza. In neonatal cardiac fibroblast, SalA inhibited fibroblast migration, blocked myofibroblast transformation, inhibited secretion of intercellular adhesion molecule (ICAM), interleukin-6 (IL-6) and soluble vascular cell adhesion molecule-1 (sVCAM-1) as well as collagen induced by MMP-9 CD. Functional effects of SalA inhibition on MMP-9 was further confirmed in cultured cardiac H9c2 cell overexpressing MMP-9 in vitro and in heart of spontaneously hypertensive rats (SHR) in vivo. Moreover, SalA treatment in SHR resulted in decreased heart fibrosis and attenuated heart hypertrophy. These results indicated that SalA is a novel inhibitor of MMP-9, thus playing an inhibitory role in hypertensive fibrosis. Further studies to develop SalA and its analogues for their potential clinical application of cardioprotection are warranted.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. jiangbh@mail.shcnc.ac.cn
authors.forename: Baohong
authors.initials: B
authors.lastname: Jiang
authors.forename: Defang
authors.initials: D
authors.lastname: Li
authors.forename: Yanping
authors.initials: Y
authors.lastname: Deng
authors.forename: Fukang
authors.initials: F
authors.lastname: Teng
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Song
authors.initials: S
authors.lastname: Xue
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Kong
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.forename: Wengang
authors.initials: W
authors.lastname: Yang
authors.forename: Jun
authors.initials: J
authors.lastname: Yin
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Wanying
authors.initials: W
authors.lastname: Wu
authors.forename: Xuan
authors.initials: X
authors.lastname: Liu
authors.forename: De-an
authors.initials: DA
authors.lastname: Guo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002109:Caffeic Acids / Q000494:pharmacology* / Q000627:therapeutic use*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism; D007773:Lactates / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR
chemical_list: D002109:Caffeic Acids; D007773:Lactates; D061965:Matrix Metalloproteinase Inhibitors; C066201:salvianolic acid A; D020780:Matrix Metalloproteinase 9