Cardiac fibroblasts (CFs) regulate myocardial remodeling by proliferating, 
differentiating, and secreting extracellular matrix proteins. Prolonged 
activation of CFs leads to cardiac fibrosis and reduced myocardial contractile 
function. Resveratrol (RES) exhibits a number of cardioprotective properties; 
however, the possibility that this compound affects CF function has not been 
considered. The current study tests whether RES directly influences the growth 
and proliferation of CFs and differentiation to the hypersecretory myofibroblast 
phenotype. Pretreatment of CFs with RES (5-25 microM) inhibited basal and ANG 
II-induced extracellular signal-regulated kinase (ERK) 1/2 and ERK kinase 
activation. This inhibition by RES reduced basal proliferation and blocked ANG 
II-induced growth and proliferation of CFs in a concentration-dependent manner, 
as measured by [(3)H]leucine and [(3)H]thymidine incorporation, respectively. 
RES pretreatment attenuated ERK phosphorylation when CFs were stimulated with 
0.2 nM epidermal growth factor (EGF), a concentration at which EGF-induced ERK 
activation over basal was similar to the phosphorylation induced by 100 nM ANG 
II. Akt phosphorylation in CFs was unaffected by treatment with either 100 nM 
ANG II or 25 microM RES. Pretreatment of CFs with RES also reduced both ANG II- 
and transforming growth factor-beta-induced CF differentiation to the 
myofibroblast phenotype, indicated by a reduction in alpha-smooth muscle actin 
expression and stress fiber organization in CFs. This study identifies RES as an 
anti-fibrotic agent in the myocardium by limiting CF proliferation and 
differentiation, two critical steps in the pathogenesis of cardiac fibrosis.