title: Apigenin attenuates neointima formation via suppression of vascular smooth muscle cell phenotypic transformation.
abstract: Abnormal proliferation, migration, and phenotypic modulation of vascular smooth muscle cells (VSMCs) are critical factors in neointima formation during restenosis. The purpose of this study is to determine the efficacy and possible cell signaling mechanisms of apigenin in VSMC activation induced by platelet-derived growth factor (PDGF)-BB and injury-induced neointima formation. Our data revealed a dose-dependent apigenin inhibition of PDGF-BB-induced proliferation of VSMCs by arresting cells in G0/G1-phase of the cell cycle as determined using 5-bromo-2'-deoxyuridine incorporation and flow cytometry. This was associated with the inhibition of cyclin-dependent kinase (CDK) 4,6 expression and an increase in p27Kip1 levels in PDGF-stimulated VSMCs. Moreover, apigenin was also found to regulate PDGF-induced migration and expression of smooth-muscle-specific contractile markers. Mechanistically, the PDGF-BB-induced phosphorylation of PDGF-receptor β (PDGF-Rβ), Akt/glycogen synthase kinase(GSK)3β, extracellular signal-regulated kinase1/2 (ERK1/2), and signal transducers and activators of transcription 3 (STAT3) is negatively modulated by apigenin. For the in vivo studies using a mouse carotid arterial injury model, the administration of apigenin resulted in a significant inhibition of the neointima/media ratio and proliferating cell nuclear antigen (PCNA)-positive cells. These results demonstrate that apigenin can suppress PDGF-induced VSMC activation and neointima hyperplasia after vascular injury; these beneficial effects are probably the result of the blockade of PDGF-Rβ phosphorylation and its downstream signal transduction, including the Akt/GSK-3β, ERK1/2, and STAT3 pathways. The results suggest that apigenin may be a potential therapeutic candidate for the prevention of restenosis.
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.
authors.forename: Hongjing
authors.initials: H
authors.lastname: Guan
authors.forename: Lu
authors.initials: L
authors.lastname: Gao
authors.forename: Lihua
authors.initials: L
authors.lastname: Zhu
authors.forename: Ling
authors.initials: L
authors.lastname: Yan
authors.forename: Mingyue
authors.initials: M
authors.lastname: Fu
authors.forename: Changgui
authors.initials: C
authors.lastname: Chen
authors.forename: Xuan
authors.initials: X
authors.lastname: Dong
authors.forename: Lang
authors.initials: L
authors.lastname: Wang
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000818:Animals; D047310:Apigenin / Q000494:pharmacology*; D000077214:Becaplermin; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D004261:DNA Replication; D015536:Down-Regulation / Q000187:drug effects; D007150:Immunohistochemistry; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D017539:Tunica Intima / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism
chemical_list: D010982:Platelet-Derived Growth Factor; D018809:Proliferating Cell Nuclear Antigen; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D047310:Apigenin