Forkhead Transcription Factors Inhibit Vascular Smooth Muscle Cell Proliferation and Neointimal Hyperplasia
| Autor: | Katherine Spokes, Md. Ruhul Abid, Shaodong Guo, Christiane Ferran, Kiichiro Yano, William C. Aird, Virendra I. Patel, Gautam V. Shrikhande |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
medicine.medical_specialty
Vascular smooth muscle medicine.medical_treatment Active Transport Cell Nucleus Becaplermin Apoptosis Cell Cycle Proteins Nerve Tissue Proteins FOXO1 Biochemistry Muscle Smooth Vascular Rats Sprague-Dawley Internal medicine medicine Animals Humans Insulin-Like Growth Factor I Phosphorylation Molecular Biology Cells Cultured Cell Proliferation Platelet-Derived Growth Factor Neointimal hyperplasia Hyperplasia biology Forkhead Box Protein O1 Tumor Necrosis Factor-alpha Cell growth Tumor Suppressor Proteins Growth factor Forkhead Box Protein O3 Nuclear Proteins FOXO Family Forkhead Transcription Factors Proto-Oncogene Proteins c-sis Cell Biology Cell cycle medicine.disease Rats DNA-Binding Proteins Endocrinology biology.protein Cancer research Tunica Intima Cyclin-Dependent Kinase Inhibitor p27 Platelet-derived growth factor receptor Signal Transduction Transcription Factors |
| Zdroj: | Journal of Biological Chemistry. 280:29864-29873 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m502149200 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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