title: Forkhead transcription factors inhibit vascular smooth muscle cell proliferation and neointimal hyperplasia.
abstract: Vascular smooth muscle cell (VSMC) proliferation and migration contribute significantly to atherosclerosis, postangioplasty restenosis, and transplant vasculopathy. Forkhead transcription factors belonging to the FoxO subfamily have been shown to inhibit growth and cell cycle progression in a variety of cell types. We hypothesized that forkhead proteins may play a role in VSMC biology. Under in vitro conditions, platelet-derived growth factor (PDGF)-BB, tumor necrosis factor-alpha, and insulin-like growth factor 1 stimulated phosphorylation of FoxO in human coronary artery smooth muscle cells via MEK1/2 and/or phosphatidylinositol 3-kinase-dependent signaling pathways. PDGF-BB, tumor necrosis factor-alpha, and insulin-like growth factor 1 treatment resulted in the nuclear exclusion of FoxO, whereas PDGF-BB alone down-regulated the FoxO target gene, p27(kip1), and enhanced cell survival and progression through the cell cycle. These effects were abrogated by overexpression of a constitutively active, phosphorylation-resistant mutant of the FoxO family member, TM-FKHRL1. The anti-proliferative effect of TM-FKHRL1 was partially reversed by small interfering RNA against p27(kip1). In a rat balloon carotid arterial injury model, adenovirus-mediated gene transfer of FKHRL1 caused an increase in the expression of p27(kip1) in the VSMC and inhibition of neointimal hyperplasia. These data suggest that FoxO activity inhibits VSMC proliferation and activation and that this signaling axis may represent a therapeutic target in vasculopathic disease states.
authors.affiliation: Center for Vascular Biology Research, Department of Medicine, Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Md Ruhul
authors.initials: MR
authors.lastname: Abid
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Yano
authors.forename: Shaodong
authors.initials: S
authors.lastname: Guo
authors.forename: Virendra I
authors.initials: VI
authors.lastname: Patel
authors.forename: Gautam
authors.initials: G
authors.lastname: Shrikhande
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Spokes
authors.forename: Christiane
authors.initials: C
authors.lastname: Ferran
authors.forename: William C
authors.initials: WC
authors.lastname: Aird
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D000077214:Becaplermin; D018797:Cell Cycle Proteins / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004268:DNA-Binding Proteins / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D006801:Humans; D006965:Hyperplasia; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins / Q000502:physiology*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics; D017539:Tunica Intima / Q000473:pathology*
chemical_list: C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; C499515:FOXO3 protein, rat; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; C074639:Foxo1 protein, rat; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077214:Becaplermin; D007334:Insulin-Like Growth Factor I