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bioRxiv · 10.1101/2022.12.20.521220

Effect of flavonoids hydroxygenkwanin on vascular smooth muscle cell proliferation, migration, and neointimal formation

Chen, C.-C.·Lin, M.-S.·Chen, P.-Y.·Leu, Y.-L.·Wang, S.-H.
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Abstract

BackgroundRestenosis and atherosclerosis are chronic inflammatory disease. Abnormal vascular smooth muscle cell (VSMC) proliferation and migration play crucial roles in neointimal hyperplasia and restenosis progression in response to stimulation with various inflammatory cytokines, such as platelet-derived growth factor-BB (PDGF-BB) and tumour necrosis factor- (TNF-). Hydroxygenkwanin (HGK) exerts remarkable anti-inflammatory, antitumour, antiproliferative and antimigratory effects. The aim of the study was to evaluate and elucidate the therapeutic effect and regulatory mechanism of HGK on neointimal hyperplasia. MethodsTo determine the therapeutic effects of HGK in PDGF-BB- or TNF--treated VSMCs, MTT assays, Western blotting analysis, cell cycle analysis, BrdU incorporation assay, wound healing assay and adhesion assay were performed in vitro. A docking assay was also used to elucidate the mechanism underlying the regulatory effect of HGK. Histological and immunohistochemical staining of denuded femoral arteries was conducted to elucidate the therapeutic effect of HGK in an in vivo assay. ResultsHGK inhibited the abnormal proliferation, migration, and inflammation of PDGF-BB- or TNF--treated VSMCs through regulation of the PDK1/AKT/mTOR pathway. In addition, HGK promoted circulating endothelial progenitor cell (EPC) chemotaxis. In an in vivo assay, HGK dramatically enhanced re-endothelization and reduced neointimal hyperplasia after femoral artery denudation with a guide wire in mice. ConclusionsIn the present study, HGK decreased the PDGF-BB- or TNF--induced abnormal proliferation, migration and inflammation in VSMCs and improved re-endothelialization and neointimal hyperplasia in denuded femoral arteries. These results provide a novel potential treatment for restenosis in the future. Graphic abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY HGK decreases VSMC abnormal proliferation, migration and inflammation through PDK1/AKT/mTOR/S6K inhibition and promotes EPC chemotaxis and reendothelialization. HGK is a potential therapeutic candidate for intimal hyperplasia and restenosis. C_FIG_DISPLAY

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Chen, C.-C., Lin, M.-S., Chen, P.-Y., Leu, Y.-L., Wang, S.-H.. 2022-12-20. Effect of flavonoids hydroxygenkwanin on vascular smooth muscle cell proliferation, migration, and neointimal formation. https://doi.org/10.1101/2022.12.20.521220

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