Indole-3-carbinol blocks platelet-derived growth factor-stimulated vascular smooth muscle cell function and reduces neointima formation in vivo.
The purpose of this study was to determine the effect and associated cell signaling mechanisms of indole-3-carbinol (I3C) on platelet-derived growth factor (PDGF)-BB-induced proliferation and migration of cultured vascular smooth muscle cells (VSMCs) and neointima formation in a carotid injury model. Our data demonstrated that I3C inhibited PDGF-BB-induced proliferation of VSMCs in a dose-dependent manner without causing cell cytotoxicity, as assessed by 5-bromo-2'-deoxyuridine incorporation and WST-1 assays. Further studies revealed that the antiproliferative effect of I3C was caused by the arrest of cells in both the G0/G1 and S phases. Moreover, I3C treatment inhibited migration of VSMCs and partly reversed the expression of smooth-muscle-specific contractile markers. We also demonstrated that I3C-induced growth inhibition was associated with an inhibition of the expression of cyclin D1 and cyclin-dependent kinase 4/6, as well as an increase in p27(Kip1) levels in PDGF-stimulated VSMCs. These beneficial effects of I3C on VSMCs appeared to be at least partly mediated by the inhibition of Akt and the subsequent activation of glycogen synthase kinase (GSK) 3β. Furthermore, using a mouse carotid artery injury model, we found that treatment with 150 mg/kg I3C resulted in a significant reduction of the neointima/media ratio and cells positive for proliferating cell nuclear antigen. These results demonstrate that I3C can suppress the proliferation and migration of VSMCs and neointima hyperplasia after vascular injury via inhibition of the Akt/GSK3β pathway and suggest that this might be feasible as part of a therapeutic strategy for vascular proliferative diseases.
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Cardiovascular Research Institute of Wuhan University, Wuhan 430060, PR China.
Hongjing
H
Guan
Changgui
C
Chen
Lihua
L
Zhu
Changping
C
Cui
Yuanyuan
Y
Guo
Mingyue
M
Fu
Lang
L
Wang
Qizhu
Q
Tang
D000818:Animals; D000077214:Becaplermin; D020212:Carotid Artery Injuries / Q000188:drug therapy / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D058426:Neointima / Q000188:drug therapy*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects
C530106:Ccnd1 protein, rat; D007211:Indoles; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077214:Becaplermin; C016517:indole-3-carbinol