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- W2918623009 abstract "Neointimal formation is a hallmark of occlusive disorders such as atherosclerosis, post-angioplasty restenosis, vein graft, and allograft vasculopathy. Upon vessel injury, increased growth factor secretion augments focal adhesion kinase (FAK) activity to promote vascular smooth muscle cell (VSMC) proliferation. However, the molecular mechanism of how FAK contributes to intimal hyperplasia remains unknown. To test the role of FAK activity in VSMC proliferative diseases, we performed femoral arterial wire injury and orally administered a FAK inhibitor (VS-4718) twice daily. FAK inhibition significantly reduced intimal hyperplasia compared to vehicle-treated mice 4 weeks after injury. We found that platelet-derived growth factor (PDGF) activated FAK and increased GATA-binding protein 4 (GATA4) expression which is correlated with VSMC proliferation, whereas FAK inhibition abolished the PDGF-induced GATA4 upregulation. Further, chromatin immunoprecipitation (ChIP) revealed that GATA4 binds the mouse cyclin D1 promoter to enhance cyclin D1 transcription, leading to VSMC proliferation via G1 to S cell cycle progression. Importantly, GATA4 and cyclin D1 expression were increased upon vascular injury parallel with increased FAK activity in vehicle-treated mice, but not changed in FAK inhibitor-treated mice. Mechanistically, FAK inhibition reduces VSMC proliferation through increased nuclear FAK, which can bind and turnover GATA4. Genetic FAK kinase-dead (KD) mice (ERT2-Myh11-Cre) developed less intimal thickening following wire injury, implicating VSMC-specific FAK activity is critical for VSMC proliferation. FAK KD VSMCs also showed increased nuclear FAK, decreased GATA4 and cyclin D1 levels compared to FAK WT. This study has uncovered the importance of GATA4 and nuclear FAK in VSMC hyperplasia." @default.
- W2918623009 created "2019-03-11" @default.
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- W2918623009 date "2018-08-03" @default.
- W2918623009 modified "2023-09-27" @default.
- W2918623009 title "Abstract 307: Focal Adhesion Kinase Activity and Nuclear Localization Controls Vascular Smooth Muscle Cell Proliferation and Intimal Hyperplasia Through a GATA4-Cyclin D1 Axis" @default.
- W2918623009 doi "https://doi.org/10.1161/res.123.suppl_1.307" @default.
- W2918623009 hasPublicationYear "2018" @default.
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