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Rubiarbonone C inhibits platelet‐derived growth factor‐induced proliferation and migration of vascular smooth muscle cells through the focal adhesion kinase, MAPK and STAT3 Tyr 705 signalling pathways
Author(s) -
Park HyunSoo,
Quan Khong Trong,
Han JooHui,
Jung SangHyuk,
Lee DoHyung,
Jo Eunji,
Lim TaeWan,
Heo KyungSun,
Na MinKyun,
Myung ChangSeon
Publication year - 2017
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13986
Subject(s) - focal adhesion , platelet derived growth factor receptor , vascular smooth muscle , mapk/erk pathway , microbiology and biotechnology , platelet derived growth factor , cell growth , growth factor , kinase , cell migration , chemistry , signal transduction , biology , cancer research , endocrinology , cell , biochemistry , receptor , smooth muscle
Background and Purpose The proliferation and migration of vascular smooth muscle cells (VSMCs) induced by platelet‐derived growth factor (PDGF) are important steps in cardiovascular diseases, including neointimal lesion formation, myocardial infarction and atherosclerosis. Here, we evaluated the rubiarbonone C‐mediated signalling pathways that regulate PDGF‐induced VSMC proliferation and migration. Experimental Approach Cell proliferation and migration were measured in cells treated with rubiarbonone C followed by PDGF BB using the MTT assay, [ 3 H]‐thymidine incorporation, flow cytometry and wound‐healing migration assay, MMP gelatin zymography, a fluorescence assay for F‐actin. Western blotting of molecules including MAPK, focal adhesion kinase (FAK) and STAT3 and an immunofluorescence assay using anti‐PCNA and ‐STAT3 antibodies were performed to evaluate rubiarbonone C signalling pathway(s). The medial thickness of the carotid artery was evaluated using a mouse carotid ligation model. Key Results Rubiarbonone C inhibited PDGF‐induced VSMC proliferation and migration and diminished the ligation‐induced increase in medial thickness of the carotid artery. In PDGF‐stimulated VSMCs rubiarbonone C decreased the following: (i) levels of cyclin‐dependent kinases, cyclins, PCNA and hyperphosphorylated retinoblastoma protein; (ii) levels and activity of MMP2 and MMP9; (iii) activation of MAPK; (iv) F‐actin reorganization, by reducing FAK activation; (v) activation of STAT3. Conclusions and Implications These findings suggest that rubiarbonone C inhibits the proliferation and migration of VSMCs by inhibiting the FAK, MAPK and STAT3 signalling pathways. Therefore, rubiarbonone C could be a good candidate for the treatment of cardiovascular disease.