Vascular Protective Effects of Alcohol - Role of Notch

酒精的血管保护作用 - Notch 的作用

基本信息

  • 批准号:
    9977944
  • 负责人:
  • 金额:
    $ 34.65万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-08-01 至 2022-07-31
  • 项目状态:
    已结题

项目摘要

Abstract     Moderate consumption of alcohol (EtOH) is a negative risk factor for cardiovascular disease but the precise mechanisms involved have not been elucidated. Pivotal to the initiation of vessel disease is endothelial cell (EC) dysfunction or loss. Subsequently, the growth and migration of vascular smooth muscle cells (SMC) are key processes in atherosclerotic plaque development, contributing to intima-medial thickening and vessel stenosis. Given the key role of both EC and SMC in the pathophysiology of atherosclerosis, effects of EtOH on these vascular cells are, thus, of considerable clinical interest. In this context Notch signaling has emerged as a novel potential target for alcohol. Repression of Notch signaling in arterial EC unlocks pro-inflammatory and pro-atherogenic signals that contribute to the initiation of atherosclerosis. Moreover, Notch signaling drives the differentiation of adult SMC from a contractile to a proliferative phenotype. Studies in animal models demonstrate that Notch signaling is stimulated following experimentally induced vascular injury, and point to a preferential role for SMC Notch 1 in mediating neointimal formation. We have shown that alcohol restrains SMC proliferation in vitro by inhibiting Notch signaling. In apparent contrast, alcohol stimulates Notch signaling and angiogenic activity in EC, while inhibiting monocyte chemoattractant protein-1 expression. These data highlight a differential effect of alcohol on Notch signaling in vascular EC and SMC - stimulatory and inhibitory, respectively, and further, implicate the Notch pathway in mediating both alcohols maintenance of an anti- atherogenic EC phenotype and it's attenuation of SMC proliferation, actions that might be considered synergistically atheroprotective. Indeed, moderate alcohol consumption ameliorates remodeling and plaque formation in injured mouse arteries. Recently, in SMC, we demonstrated a novel inhibitory effect of alcohol specifically on the γ-secretase cleavage activity that is critical for Notch signaling.  Our preliminary data now indicate that EtOH enhances γ-secretase activity in EC. Therefore, the central hypothesis of our proposal is that moderate alcohol consumption protects against atherogenesis by differential yet synergistic effects on Notch signaling at the level of γ-secretase, in vascular smooth muscle and endothelial cells. To test our hypothesis, and delineate the mechanisms involved, we will use a novel in vitro `mock artery' stented and seeded with SMC cells under cyclic strain conditions, as well as endothelial cells exposed to physiologic and pathologic shear stresses in artificial capillaries, in conjunction with in vivo studies utilizing transgenic mice and a `flow-restriction' model of atherosclerosis. Deciphering the mechanisms whereby alcohol may protect against cardiovascular disease is of major clinical significance and will uncover new therapy targets for this common cause of morbidity and mortality.
摘要     适量饮酒(EtOH)是心血管疾病的一个负面风险因素,但确切的风险因素是 所涉及的机制尚未阐明。血管病变的发生首先是内皮细胞 (EC)功能障碍或丧失。随后,血管平滑肌细胞(SMC)的生长和迁移被抑制。 动脉粥样硬化斑块发展的关键过程,有助于内膜-中层增厚和血管 狭窄鉴于EC和SMC在动脉粥样硬化病理生理学中的关键作用, 因此,这些血管细胞具有相当大的临床意义。在这种情况下,Notch信号已经出现, 酒精的一个新的潜在目标。动脉EC中Notch信号传导的抑制释放促炎性和 促动脉粥样硬化信号,有助于动脉粥样硬化的起始。此外,Notch信号驱动 在一些实施方案中,所述方法包括将成体SMC从收缩表型分化为增殖表型。动物模型研究 证明Notch信号在实验诱导的血管损伤后被刺激,并指出 SMC Notch 1在介导新生内膜形成中的优先作用。我们已经证明酒精抑制 通过抑制Notch信号通路抑制SMC增殖。与此形成鲜明对比的是,酒精刺激Notch信号传导, 和EC中的血管生成活性,同时抑制单核细胞趋化蛋白-1表达。这些数据 强调了酒精对血管EC和SMC中Notch信号传导不同作用-刺激和抑制, 进一步,暗示Notch途径介导两种醇类维持抗- 致动脉粥样硬化的EC表型及其对SMC增殖的抑制作用, 协同抗动脉粥样硬化。事实上,适量饮酒可以改善重塑和斑块 在受损的小鼠动脉中形成。最近,在SMC中,我们证明了酒精的新抑制作用 特别是对Notch信号传导至关重要的γ-分泌酶切割活性。 表明EtOH可增强EC中γ-分泌酶活性。因此,我们建议的中心假设是 适度饮酒通过对动脉粥样硬化的不同但协同的影响来防止动脉粥样硬化的发生, 血管平滑肌和内皮细胞中γ-分泌酶水平的Notch信号传导。来测试我们 假设,并描述所涉及的机制,我们将使用一种新的体外“模拟动脉”支架, 在循环应变条件下用SMC细胞接种,以及暴露于生理和 人工毛细血管中的病理剪切应力,结合使用转基因小鼠的体内研究, 动脉粥样硬化的“血流限制”模型。解读酒精可以防止 心血管疾病具有重要的临床意义,并将为这种常见的疾病发现新的治疗靶点。 发病和死亡的原因。

项目成果

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EILEEN M. REDMOND其他文献

EILEEN M. REDMOND的其他文献

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{{ truncateString('EILEEN M. REDMOND', 18)}}的其他基金

Alcohol Regulation of Endothelial Plasticity in Atherosclerosis
酒精对动脉粥样硬化内皮可塑性的调节
  • 批准号:
    10585070
  • 财政年份:
    2023
  • 资助金额:
    $ 34.65万
  • 项目类别:
Biphasic Regulation of Endothelial Transdifferentiation by Alcohol and Its Impact on Vascular Disease
酒精对内皮转分化的双相调节及其对血管疾病的影响
  • 批准号:
    10771448
  • 财政年份:
    2023
  • 资助金额:
    $ 34.65万
  • 项目类别:
Vascular Protective Effects of Alcohol - Role of Notch
酒精的血管保护作用 - Notch 的作用
  • 批准号:
    9380598
  • 财政年份:
    2017
  • 资助金额:
    $ 34.65万
  • 项目类别:
Vascular Protective Effects of Alcohol - Role of Notch
酒精的血管保护作用 - Notch 的作用
  • 批准号:
    10219789
  • 财政年份:
    2017
  • 资助金额:
    $ 34.65万
  • 项目类别:
Alcohol Regulation of Resident Vascular Stem Cells.
驻留血管干细胞的酒精调节。
  • 批准号:
    9107329
  • 财政年份:
    2015
  • 资助金额:
    $ 34.65万
  • 项目类别:
Role of Nogo-B in Mediating the Vascular Effects of Alcohol
Nogo-B 在介导酒精血管效应中的作用
  • 批准号:
    8538869
  • 财政年份:
    2012
  • 资助金额:
    $ 34.65万
  • 项目类别:
Role of Nogo-B in Mediating the Vascular Effects of Alcohol
Nogo-B 在介导酒精血管效应中的作用
  • 批准号:
    8242915
  • 财政年份:
    2012
  • 资助金额:
    $ 34.65万
  • 项目类别:
Alcohol Regulation of Smooth Muscle Migration and Growth
酒精对平滑肌迁移和生长的调节
  • 批准号:
    6730207
  • 财政年份:
    1999
  • 资助金额:
    $ 34.65万
  • 项目类别:
Alcohol Regulation of Smooth Muscle Migration and Growth
酒精对平滑肌迁移和生长的调节
  • 批准号:
    7072860
  • 财政年份:
    1999
  • 资助金额:
    $ 34.65万
  • 项目类别:
ALCOHOL REGULATION OF SMOOTH MUSCLE MIGRATION AND GROWTH
酒精对平滑肌迁移和生长的调节
  • 批准号:
    6168544
  • 财政年份:
    1999
  • 资助金额:
    $ 34.65万
  • 项目类别:

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