한빛사 논문
Kyuho Jeong1,†, Jung-Hyun Kim2,†, James M Murphy1,†, Hyeonsoo Park3, Su-Jeong Kim1, Yelitza Rodriguez4, Hyunkyung Kong5, Chungsik Choi6, Jun-Lin Guan7, Joan M Taylor8, Thomas M Lincoln6, William T Gerthoffer9, Jun-Sub Kim10, Eun-Young Erin Ahn1, David D Schlaepfer11, and Ssang-Taek Steve Lim1,*
1Biochemistry and Molecular Biology, University of South Alabama College of Medicine
2Mitchell Cancer Center, University of South Alabama College of Medicine,
3Biochemistry and Molecular Biology, University of South Alabama College of Medicine
4Biochemistry and Molecular Biology, University of South Alabama College of Medicine
5Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
6Physiology, University of South Alabama College of Medicine
7Cancer Biology, University of Cincinnati College of Medicine
8Pathology, The University of North Carolina at Chapel Hill
9University of Nevada, Reno
10Biotechnology, Korea National University of Transportation
11Obstetrics, Gynecology, and Reproductive Medicine, University of California, San Diego Moores Cancer Center
*Corresponding Author
†Equal contribution
Abstract
Rationale: Neointimal hyperplasia is characterized by excessive accumulation of vascular smooth muscle cells (SMCs) leading to occlusive disorders such as atherosclerosis and stenosis. Blood vessel injury increases growth factor secretion and matrix synthesis, which promotes SMC proliferation and neointimal hyperplasia via focal adhesion kinase (FAK).
Objective: To understand the mechanism of FAK action in SMC proliferation and neointimal hyperplasia.
Methods and Results: Using combined pharmacological FAK catalytic inhibition (VS-4718) and SMC-specific FAK kinase-dead (KD, Myh11-Cre-ERT2) mouse models, we report that FAK regulates SMC proliferation and neointimal hyperplasia in part by governing GATA4-cyclin D1 signaling. Inhibition of FAK catalytic activity facilitates FAK nuclear localization, which is required for proteasome-mediated GATA4 degradation in the cytoplasm. Chromatin immunoprecipitation identified GATA4 binding to the mouse cyclin D1 promoter and loss of GATA4-mediated cyclin D1 transcription diminished SMC proliferation. Stimulation with platelet-derived growth factor or serum activated FAK and redistributed FAK from the nucleus to cytoplasm, leading to concomitantly increased GATA4 protein and cyclin D1 expression. In a femoral artery wire injury model, increased neointimal hyperplasia was observed in parallel with elevated FAK activity, GATA4 and cyclin D1 expression following injury in control, but not in VS-4718-treated and SMC-specific FAK-KD mice. Finally, lentiviral shGATA4 knockdown in the femoral artery wire injury significantly reduced cyclin D1 expression, SMC proliferation, and neointimal hyperplasia compared to control mice.
Conclusions: Nuclear enrichment of FAK by inhibition of FAK catalytic activity during vessel injury blocks SMC proliferation and neointimal hyperplasia through regulation of GATA4-mediated cyclin D1 transcription.
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