Nuclear FAK-mediated VSMC differentiation via epigenetic reprograming invascular diseases

通过表观遗传重编程血管疾病中核 FAK 介导的 VSMC 分化

基本信息

  • 批准号:
    10584581
  • 负责人:
  • 金额:
    $ 47.54万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-05-16 至 2026-03-31
  • 项目状态:
    未结题

项目摘要

VSMCs dedifferentiate into a proliferative state upon vessel injury or transdifferentiate into macrophage-like cells (MLCs) during atherosclerosis progression. VSMC phenotypic switching are driven by multiple transcriptional and epigenetic changes that lead to increased proliferation with reduced contractile gene expression and increased matrix production, which is detrimental to atherosclerotic lesions, direct interventional studies that target this process have been lacking. Increased matrix and growth factors alter integrin signaling and leads to aberrant focal adhesion kinase (FAK) activation, which may promote VSMC phenotypic switching. We demonstrated that FAK is inactive and primarily localized in the nuclei of VSMCs of healthy arteries. However, vessel injury promoted FAK activation and cytoplasmic relocalization, which increased cyclin D1 transcription and cell cycling. While we found that inhibition of FAK activity in VSMCs induced nuclear localization of FAK and increased contractile gene transcription, the underlying mechanism by which FAK regulates the contractile genes is not known. We have identified DNA methyltransferase 3A (DNMT3A) and the nucleosome remodeling and deacetylase (NuRD) complex, two key epigenetic repression machineries, as nuclear FAK-interacting partners in VSMCs. FAK inhibition decreased DNMT3A and NuRD component expression, which was associated with decreased DNA methylation and increased active histone marks within contractile gene promoters. Using genetic FAK cytoplasmic (Cyto) restricted VSMCs, we found that nuclear FAK is required for reducing DNMT3A/NuRD and for increasing contractile gene expression. Additionally, ApoE-/-;FAK-Cyto mice showed increased atherosclerosis compared to WT mice, suggesting that active cytoplasmic FAK exacerbates atherosclerosis. Further, FAK showed increased cytoplasmic localization and activity within human atherosclerotic lesions compared to healthy specimens. Importantly, FAK inhibitor reduced advanced atherosclerotic lesions in ApoE-/- mice, which was associated with reduced DNMT3A and NuRD component expression with increased ACTA2+ cells in the fibrous cap. Our hypothesis is that FAK catalytic inhibition forces FAK nuclear localization and promotes VSMC differentiation via reduced expression of epigenetic regulators DNMT3A and NuRD complex. Aim 1 will elucidate the molecular mechanism of nuclear FAK-mediated VSMC phenotypic switching via epigenetic modulation of DNA methylation, chromatin remodeling, and histone modification. Aim 2 will investigate the role of DNMT3A and the NuRD complex in VSMC dedifferentiation upon vascular injury using both DNMT3A and NuRD genetic models. Aim 3 will evaluate the effect of FAK inhibition on blocking VSMC transdifferentiation and promoting plaque stability in early and advanced atherosclerosis. This study will provide new insights into VSMC phenotype switching via FAK-mediated epigenetic control through DNMT3A and NuRD complex stability. The therapeutic potential of FAK inhibitors in alleviating intimal thickening in vascular injury and atherosclerosis will also be assessed.
血管平滑肌细胞在血管损伤后去分化为增殖状态或转分化为巨噬细胞样 细胞(MLCs)在动脉粥样硬化的进展。VSMC表型转换是由多种 转录和表观遗传变化导致增殖增加,收缩基因减少 表达和增加的基质生产,这是有害的动脉粥样硬化病变,直接 缺乏针对这一过程的干预性研究。基质和生长因子的增加 整合素信号传导,并导致异常的粘着斑激酶(FAK)激活,这可能促进VSMC 表型转换我们证明FAK是无活性的,主要定位于VSMCs的细胞核, 健康的动脉然而,血管损伤促进FAK活化和胞浆重定位, 增加细胞周期蛋白D1转录和细胞周期。虽然我们发现抑制VSMCs中FAK活性 诱导FAK的核定位和增加收缩基因转录,其潜在机制是 FAK调节收缩基因的机制尚不清楚。我们已经鉴定出DNA甲基转移酶3A DNMT 3A和核小体重塑和脱乙酰酶(NuRD)复合物,两个关键的表观遗传抑制 机械,作为VSMC中的核FAK相互作用伙伴。FAK抑制降低了DNMT 3A和NuRD 组分表达,这与DNA甲基化降低和活性组蛋白增加有关 收缩基因启动子内的标记。使用遗传FAK胞质(Cyto)限制的VSMCs,我们发现 核FAK是减少DNMT 3A/NuRD和增加收缩基因表达所必需的。 此外,与WT小鼠相比,ApoE-/-;FAK-Cyto小鼠显示动脉粥样硬化增加,表明 活性细胞质FAK加剧动脉粥样硬化。此外,FAK表现出增加的细胞质定位 以及与健康样本相比在人动脉粥样硬化病变中的活性。重要的是,FAK抑制剂 减少ApoE-/-小鼠中的晚期动脉粥样硬化病变,这与DNMT 3A减少有关, NuRD组分表达,纤维帽中ACTA 2+细胞增加。我们假设FAK 催化抑制迫使FAK核定位并通过减少表达促进VSMC分化 DNMT 3A和NuRD复合物的表达。目的1将阐明 核FAK介导的VSMC表型转换通过DNA甲基化、染色质 重塑和组蛋白修饰。目的2将研究DNMT 3A和NuRD复合物在 使用DNMT 3A和NuRD遗传模型在血管损伤后VSMC去分化。目标3将 评估FAK抑制对阻断VSMC转分化和促进斑块稳定性的作用, 早期和晚期动脉粥样硬化。这项研究将提供新的见解VSMC表型转换, 通过DNMT 3A和NuRD复合物稳定性的FAK介导的表观遗传控制。的治疗潜力 还将评估FAK抑制剂在减轻血管损伤和动脉粥样硬化中的内膜增厚方面的作用。

项目成果

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Steve Lim其他文献

Steve Lim的其他文献

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{{ truncateString('Steve Lim', 18)}}的其他基金

Nuclear FAK-mediated VSMC differentiation via epigenetic reprograming invascular diseases
通过表观遗传重编程血管疾病中核 FAK 介导的 VSMC 分化
  • 批准号:
    10618482
  • 财政年份:
    2022
  • 资助金额:
    $ 47.54万
  • 项目类别:
FAK regulation of cholesterol influx and efflux in foam cells
FAK对泡沫细胞中胆固醇流入和流出的调节
  • 批准号:
    10729865
  • 财政年份:
    2021
  • 资助金额:
    $ 47.54万
  • 项目类别:
FAK regulation of cholesterol influx and efflux in foam cells
FAK 对泡沫细胞中胆固醇流入和流出的调节
  • 批准号:
    10640873
  • 财政年份:
    2021
  • 资助金额:
    $ 47.54万
  • 项目类别:
FAK regulation of cholesterol influx and efflux in foam cells
FAK 对泡沫细胞中胆固醇流入和流出的调节
  • 批准号:
    10278516
  • 财政年份:
    2021
  • 资助金额:
    $ 47.54万
  • 项目类别:
FAK regulation of cholesterol influx and efflux in foam cells
FAK 对泡沫细胞中胆固醇流入和流出的调节
  • 批准号:
    10427440
  • 财政年份:
    2021
  • 资助金额:
    $ 47.54万
  • 项目类别:
Role of FAK in vascular inflammation
FAK 在血管炎症中的作用
  • 批准号:
    9886279
  • 财政年份:
    2017
  • 资助金额:
    $ 47.54万
  • 项目类别:
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