Inhibition of cardiac fibroblast proliferation and myofibroblast differentiation by resveratrol

The Ohio State University, Columbus, Ohio, United States
AJP Heart and Circulatory Physiology (Impact Factor: 3.84). 04/2005; 288(3):H1131-8. DOI: 10.1152/ajpheart.00763.2004
Source: PubMed


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.

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    • "Cell proliferation was assessed via [ 3 H]thymidine incorporation using techniques previously described by Olson et al. [16]. Briefly, equal numbers of CFs were plated on 12-well tissue culture plates in immunoblot (upper panel) and densitometric analysis (lower panel) demonstrate a 2.2-fold increase in β-arrestin1 and a 2-fold increase in β-arrestin2 in HF compared to control CF. "
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