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This Article Full Text Full Text (PDF) All Versions of this Article: 288/3/H1131    most recent 00763.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (15) Citing Articles via Google Scholar Google Scholar Articles by Olson, E. R. Articles by Meszaros, J. G. Search for Related Content PubMed PubMed Citation Articles by Olson, E. R. Articles by Meszaros, J. G.

Inhibition of cardiac fibroblast proliferation and myofibroblast differentiation by resveratrol

¹Department of Physiology and Pharmacology, Northeastern Ohio Universities College of Medicine, Rootstown; and ²Department of Human Nutrition, The Ohio State University, Columbus, Ohio

Submitted 28 July 2004 ; accepted in final form 15 October 2004

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 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 [³H]leucine and [³H]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 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.

angiotensin II; fibrosis; remodeling; mitogen-activated protein kinase

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