Anti-Atherogenic Mechanisms of Drebrin

Drebrin 的抗动脉粥样硬化机制

基本信息

  • 批准号:
    10532356
  • 负责人:
  • 金额:
    $ 52.33万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-12-16 至 2024-11-30
  • 项目状态:
    已结题

项目摘要

We discovered that the actin-binding protein, Drebrin, is abundantly expressed in smooth muscle cells (SMCs) and is up-regulated in response to arterial injury in mice and to atherosclerosis in humans. Comparing WT with Dbn-/+ mice, we found that Drebrin inhibits SMC migration and proliferation, both in vitro and in vivo, through stabilization of actin filaments. In studies with SMC-specific Dbn-/- (SMC-Dbn-/-) mice, we found that SMC Drebrin limits angiotensin II-induced remodeling of the ascending aorta, in a manner that correlates with down-regulation of NADPH oxidase 1 (NOX1), decreased SMC reactive oxygen species (ROS) production and reduced vascular inflammation. Thus, Drebrin constrains not only the migratory/proliferative SMC phenotype but also the pro-inflammatory SMC phenotype evoked by vascular injury and angiotensin II. Congruently, we found that atherosclerosis is greater in SMC-Dbn-/-/Ldlr-/- than in congenic SMC-Dbn+/+/Ldlr-/- mice. Because SMC Drebrin negatively regulates atherosclerosis, our goals are to determine the mechanisms by which Drebrin regulates SMC pro-inflammatory signaling and whether enhanced SMC expression of Drebrin can inhibit atherogenesis. To this end, we performed SILAC/mass spectrometry studies on Dbn-/- and congenic WT SMCs. We found that whereas in Dbn-/- SMCs the ROS-defensive enzyme Glutathione-S-transferase µ1 (GSTM1) is down-regulated, the pro-inflammatory cytokine CX3CL1 (fractalkine) is up-regulated: thus we will investigate the role of these proteins in mediating the phenotype of Dbn-/- SMCs. Because endocytosis of NOX1 regulates ROS generation and activation of pro-inflammatory NFκB signaling and Drebrin has been shown to inhibit endocytosis, we will investigate whether Drebrin inhibits NOX1-mediated ROS generation by inhibiting endocytosis. A major focus of our studies will be pro-atherogenic SMC-derived foam cells, which SMC lineage tracing studies have shown, comprise ~40% of foam cells in atherosclerotic lesions. Our Preliminary Studies show that, compared with cognate Dbnflox/flox SMCs, Dbn-/- SMCs induced to transdifferentiate with cholesterol loading exhibited increased expression of the macrophage marker, CD68, and Kruppel-like factor 4 (KLF4), a transcription factor required for SMC-to-foam cell transdifferentiation. By grafting common carotid arteries from Dbnflox/flox and SMC-Dbn-/- mice into carotid arteries of congenic Apoe-/- mice, we also show that Drebrin deficiency augments transdifferentiation of SMCs to CD68+ cells in vivo. We will test the hypothesis that Drebrin inhibits atherogenesis by limiting SMC transdifferentiation into foam cells. To do so, we will establish whether Drebrin inhibits SMC-to-foam cell transdifferentiation and associated pro- inflammatory signaling, both in vitro and in vivo; determine if Drebrin inhibits SMC transdifferentiation through ROS-dependent mechanisms; and define the roles of GSTM1 and CX3CL1 in mediating Drebrin’s inhibitory effects on SMC transdifferentiation and pro-inflammatory signaling.
我们发现肌动蛋白结合蛋白Drebrin在平滑肌细胞(SMCs)中大量表达。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation.
  • DOI:
    10.1093/cvr/cvab156
  • 发表时间:
    2021-04
  • 期刊:
  • 影响因子:
    10.8
  • 作者:
    Jiao‐Hui Wu;Lisheng Zhang;Igor Nepliouev;L. Brian;Taiqin Huang;Kamie P Snow;B. Schickling;E. Hauser;F. Miller;N. Freedman;Jonathan A Stiber
  • 通讯作者:
    Jiao‐Hui Wu;Lisheng Zhang;Igor Nepliouev;L. Brian;Taiqin Huang;Kamie P Snow;B. Schickling;E. Hauser;F. Miller;N. Freedman;Jonathan A Stiber
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NEIL J. FREEDMAN其他文献

NEIL J. FREEDMAN的其他文献

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{{ truncateString('NEIL J. FREEDMAN', 18)}}的其他基金

Mechanisms by which Small Nucleolar RNAs Exacerbate Atherosclerosis
小核仁 RNA 加剧动脉粥样硬化的机制
  • 批准号:
    10502380
  • 财政年份:
    2022
  • 资助金额:
    $ 52.33万
  • 项目类别:
Mechanisms by which Small Nucleolar RNAs Exacerbate Atherosclerosis
小核仁 RNA 加剧动脉粥样硬化的机制
  • 批准号:
    10670399
  • 财政年份:
    2022
  • 资助金额:
    $ 52.33万
  • 项目类别:
Anti-Atherogenic Mechanisms of Drebrin
Drebrin 的抗动脉粥样硬化机制
  • 批准号:
    10318175
  • 财政年份:
    2019
  • 资助金额:
    $ 52.33万
  • 项目类别:
Regulation of Vascular Inflammatory Signaling by the Deubiquitinase USP20
去泛素酶 USP20 对血管炎症信号的调节
  • 批准号:
    9765984
  • 财政年份:
    2019
  • 资助金额:
    $ 52.33万
  • 项目类别:
Regulation of Vascular Inflammatory Signaling by the Deubiquitinase USP20
去泛素酶 USP20 对血管炎症信号的调节
  • 批准号:
    9893026
  • 财政年份:
    2019
  • 资助金额:
    $ 52.33万
  • 项目类别:
Anti-Atherogenic Mechanisms of Drebrin
Drebrin 的抗动脉粥样硬化机制
  • 批准号:
    9887940
  • 财政年份:
    2019
  • 资助金额:
    $ 52.33万
  • 项目类别:
Regulation of Vascular Inflammatory Signaling by the Deubiquitinase USP20
去泛素酶 USP20 对血管炎症信号的调节
  • 批准号:
    10349573
  • 财政年份:
    2019
  • 资助金额:
    $ 52.33万
  • 项目类别:
Regulation of Vascular Inflammatory Signaling by the Deubiquitinase USP20
去泛素酶 USP20 对血管炎症信号的调节
  • 批准号:
    10112295
  • 财政年份:
    2019
  • 资助金额:
    $ 52.33万
  • 项目类别:
Regulation of B-arrestin2's pro-atherogenic activity by the deubiquitinase USP20
去泛素酶 USP20 对 B-arrestin2 促动脉粥样硬化活性的调节
  • 批准号:
    8797106
  • 财政年份:
    2014
  • 资助金额:
    $ 52.33万
  • 项目类别:
Regulation of B-arrestin2's pro-atherogenic activity by the deubiquitinase USP20
去泛素酶 USP20 对 B-arrestin2 促动脉粥样硬化活性的调节
  • 批准号:
    8639259
  • 财政年份:
    2014
  • 资助金额:
    $ 52.33万
  • 项目类别:

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