title: 2,3,4',5-Tetrahydroxystilbene-2-O-β-D-glucoside inhibits angiotensin II-induced cardiac fibroblast proliferation via suppression of the reactive oxygen species-extracellular signal-regulated kinase 1/2 pathway.
abstract: Cardiac fibroblasts (CF) have direct and potent effects on myocardial remodelling by proliferating, differentiating and secreting extracellular matrix proteins. Prolonged activation of CF leads to cardiac fibrosis and reduces myocardial contractile function. In previous studies we showed that 2,3,4',5-tetrahydroxystilbene-2-O-β-d-glucoside (TSG) exerts cardiac protection, but the mechanism involved remains unclear. The aim of the present study was to evaluate the effects of TSG on angiotensin (Ang) II-induced CF proliferation and to explore the underlying intracellular mechanisms. Angiotensin II (100 nmol/L)-induced proliferation of rat neonatal fibroblasts was significantly inhibited by TSG (3-100 μmol/L), as evidenced by investigations of cell numbers and 5-bromodeoxyuridine (BrdU) incorporation. In addition, 30 μmol/L TSG suppressed AngII-induced expression of nuclear antigen, matrix metalloproteinase (MMP)-2 and MMP-9. Moreover, TSG attenuated AngII-induced activation of mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) 1/2. Angiotensin II (100 nmol/L)-induced generation of reactive oxygen species (ROS) was reduced by 30 μmol/L TSG, as was H(2) O(2) -induced activation of ERK1/2. However, the MEK inhibitor 50 μmol/L PD98059 did not reduce ROS generation, although it did inhibit cell proliferation. There was a significant correlation between the inhibition of ERK1/2 activation and suppression of cell proliferation by TSG. However, there were no additive effects on either the inhibition of ERK1/2 or the suppression of cell proliferation following treatment of cells with both PD98059 and TSG. In conclusion, the results of the present study suggest that TSG inhibits ERK1/2 activation, likely via buffering of ROS, and consequently suppresses cell proliferation.
authors.affiliation: Department of Pharmacology, Nantong University Medical College, Nantong, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Xiang-Fan
authors.initials: XF
authors.lastname: Chen
authors.forename: Yan-Juan
authors.initials: YJ
authors.lastname: Huang
authors.forename: Qing-Qing
authors.initials: QQ
authors.lastname: Chen
authors.forename: Yuan-Jian
authors.initials: YJ
authors.lastname: Bao
authors.forename: Weizhong
authors.initials: W
authors.lastname: Zhu
mesh_terms: D000804:Angiotensin II / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology; D005960:Glucosides / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D005960:Glucosides; D006131:Growth Inhibitors; D017382:Reactive Oxygen Species; D013267:Stilbenes; D000804:Angiotensin II; C093026:2,3,5,4'-tetrahydroxystilbene 2-O-glucopyranoside