161 RESVERATROL REDUCES VESSEL-GRAFT NEOINTIMAL FORMATION BY INDUCING ENDOTHELIAL DIFFERENTIATION OF RESIDENT PROGENITOR CELLS THROUGH A MIR-21/AKT/B-CATENIN PATHWAY. (24th May 2013)

• Record Type: Journal Article
• Authors: Campagnolo, P; Hong, X; Hu, Y; Xu, Q
• Is Part Of: Heart. Volume 99(2013)Supplement 2
• Page Start: A94
• Page End: A94
• Publication Date: 2013-05-24
• Subjects: Heart -- Diseases -- Treatment -- Periodicals; Cardiology -- Periodicals; 616.12
• DOI: 10.1136/heartjnl-2013-304019.161
• Languages: English
• ISSNs: 1355-6037

Abstract

Abstract : Background: Vessel graft failure is typically associated neointimal formation and arteriosclerosis, in which endothelial dysfunction/damage is a key event.1 Resveratrol has been shown to possess cardioprotective capacity and to reduce atherosclerosis, through its anti-oxidant and anti-apoptotic properties.2–4 However, it is unknown whether it influences the behavior of resident stem cells in the vessel wall leading to the development of arteriosclerosis. Methods and results: In the present study, the mouse model of vein grafts was established by grafting vena cava to carotid artery using a cuff technique. ApoE knockout animals were randomly assigned to two groups, one receiving a diet enriched with resveratrol and one control group on a normal diet. It was found that neointimal lesions 4 weeks postoperatively were significantly reduced in resveratrol-treated group compared to untreated controls. Immunostaining for cell components in the grafts revealed the presence of Sca-1+ progenitor cells in the lesional adventitia and neointima of vein grafts. Subsequently, Sca-1+ cells from 4-week vein grafts were cultivated and isolated. Interestingly, stem/progenitor cell differentiation into endothelial lineage was markedly increased by treatment with resveratrol in vitro. We investigated the mechanism involved in the resveratrol-induced progenitor cell differentiation and identified miR-21 as a target of resveratrol. We demonstrated that resveratrol significantly reduced miR-21 expression during endothelial differentiation of progenitor cells, which in turn reduced Akt phosphorylation. This signal cascade diminished the amount of nuclear β-catenin, ultimately inducing endothelial marker expression and tube-like formation capacity in stem/progenitor cells. Both the inhibition of miR-21 and the knockdown of β-catenin were able to resemble the effect of resveratrol application, i.e. reducing endothelial differentiation. Finally, the effect of resveratrol on progenitor cell differentiation was blunted by the overexpression of miR-21. Conclusion: We provide the first evidence that oral administration of resveratrol can reduce neointimal formation in an animal model of vein graft, by inducing re-endothelialization through progenitor cell differentiation. We established that the mechanism involved is miR-21/Akt/β-catenin dependent. These findings might contribute to explain the beneficial effect of red wine consumption on vascular disease.