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 (100nmol/L)-induced proliferation of rat neonatal fibroblasts was significantly inhibited by TSG (3-100μmol/L), as evidenced by investigations of cell numbers and 5-bromodeoxyuridine (BrdU) incorporation. In addition, 30μmol/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 (100nmol/L)-induced generation of reactive oxygen species (ROS) was reduced by 30μmol/L TSG, as was H(2) O(2) -induced activation of ERK1/2. However, the MEK inhibitor 50μmol/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.