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임쌍택
임쌍택 (Ssang-Taek Lim) 저자 이메일 보기
University of South Alabama College of Medicine
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조회 533  인쇄하기 주소복사 트위터 공유 페이스북 공유 
Nuclear Focal Adhesion Kinase Controls Vascular Smooth Muscle Cell Proliferation and Neointimal Hyperplasia Through GATA4-mediated Cyclin D1 Transcription.
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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.

논문정보
- 형식: Research article
- 게재일: 2019년 05월 (BRIC 등록일 2019-05-19)
- 연구진: 국내+국외 연구진
- 분야: Cell_Biology, Medicine, Molecular_Biology
광유전학의 과거, 현재와 미래[Neuron]
김윤석
발표: 김윤석 (Stanford University)
일자: 2020년 7월 30일 (목) 오후 02시 (한국시간)
언어: 한국어
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