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1 Department of Physiology and Pharmacology, Northeastern Ohio Universities College of Medicine, Rootstown, OH, USA
2 Department of Food Science and Technology, The Ohio State University, Columbus, OH, USA
* To whom correspondence should be addressed. E-mail: jgmeszar{at}neoucom.edu.
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 µM) inhibited basal and angiotensin II (ANG II)-induced extracellular signal-regulated kinase (ERK) 1/2 and ERK kinase (MEK) 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 3H-leucine and 3H-thymidine incorporation, respectively. RES pretreatment attenuated ERK phosphorylation when CFs were stimulated with 0.2 nM 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 µM RES. Pretreatment of CFs with RES also reduced both ANG II- and transforming growth factor 
-induced CF differentiation to the myofibroblast phenotype, indicated by a reduction in 
-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.
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