apoE, arterial biomechanics, and cardiovascular disease

apoE、动脉生物力学和心血管疾病

基本信息

  • 批准号:
    8771694
  • 负责人:
  • 金额:
    $ 45.79万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-09-01 至 2018-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Arterial stiffening is a risk factor for cardiovascular disease, but how arteries stay supple and how arterial stiffness contributes to disease are unknown. Our preliminary studies show that arterial elasticity is maintained by Apo lipoprotein E (apoE) and apoE-containing HDL through a suppressive effect on the expression of extracellular matrix genes. ApoE interrupts a mechanically driven feed-forward loop that increases the expression of collagen-I, fibronectin, and lysyl oxidase in response to substratum stiffening. These effects are independent of the apoE lipid-binding domain. Arterial stiffness is increased in apoE-null mice, this stiffening can be reduced by administration of the lysyl oxidase inhibitor, BAPN, and BAPN treatment attenuates atherosclerosis despite highly elevated cholesterol. Macrophage abundance in lesions is reduced by BAPN in vivo, and monocyte/macrophage adhesion is reduced by substratum softening in vitro. Mechanistically, we show that apoE and apoE-containing HDL inhibit Rho-GTP activity and reduce intracellular force in VSMCs. These changes in VSMC mechanics then affect ECM gene expression. Finally, we show that in addition to regulating (fibrillar) collagen-I, apoE and apoE-HDL inhibit the expression of collagen-VIII, a non-fibrillar collagen that has profound effects on VSMC function and atherosclerosis, yet is largely unexplored in terms of its mechanical properties and mechanistic effects. Overall, our data describe a completely new role for apoE and apoE-HDL that is independent of plasma cholesterol levels, intimately connected to cell and tissue mechanobiology, and causally linked to protection from atherosclerosis. We now propose three specific aims to characterize the relationships between apoE, intracellular force, matrix remodeling, and protection from atherosclerosis. In Aim 1, we will use a new micro fabrication platform of VSMC micro-tissues to study the effect of collagen-VIII on Rho-activity, contractility, ECM gene expression, and tissues stiffness in 3D. We will also use this system to determine how collagen-VIII controls the mechanical response to apoE. These in vitro studies will be complemented with an ex vivo analysis of arterial stiffness in apoE+/+ and apoE-/- arteries isolated from WT and collagen-VIII deficient mice. In Aim 2, we examine the mechanism by which stiffness controls atherosclerotic lesion development, with the particular goal of identifyin mechano-sensitive adhesion receptors that account for stiffness-dependent attachment of monocytes and macrophages to sub endothelial ECM protein. As in Aim 1, complementary in vivo experiments with existing mouse models will test the effect of arterial stiffness on monocyte abundance in vivo. Aim 3 will link the results in the first two aims by developing a new mouse model that can delete RhoA from VSMCs and establish the effect of reduced intracellular force on ECM gene expression, arterial stiffness, and atherosclerosis in vivo. This work brings together a team of three PI's (Assoian, Chen and Bendeck) with complementary expertise and an established track record of co- publication who, jointly, will establish how this novel regulatin of the ECM and VSMC mechanics by apoE provides cholesterol-independent protection against cardiovascular disease.
描述(由申请人提供):动脉硬化是心血管疾病的危险因素,但动脉如何保持柔软以及动脉硬化如何导致疾病尚不清楚。我们的初步研究表明,载脂蛋白E (apoE)和含apoE的HDL通过抑制细胞外基质基因的表达来维持动脉弹性。ApoE阻断了一个机械驱动的前馈循环,该循环增加了胶原- 1、纤维连接蛋白和赖氨酸氧化酶在基质硬化时的表达。这些作用与载脂蛋白e脂结合结构域无关。apoe缺失小鼠的动脉硬化增加,这种硬化可以通过给药赖氨酸氧化酶抑制剂BAPN来减轻,尽管高胆固醇,但BAPN治疗可以减轻动脉粥样硬化。体内BAPN可降低病变内巨噬细胞的丰度,体外基质软化可降低单核细胞/巨噬细胞粘附。在机制上,我们发现apoE和含apoE的HDL抑制VSMCs的Rho-GTP活性并降低细胞内力。VSMC机制的这些变化进而影响ECM基因的表达。最后,我们表明,除了调节(纤维)胶原- i, apoE和apoE- hdl抑制胶原- viii的表达,胶原- viii是一种对VSMC功能和动脉粥样硬化有深远影响的非纤维胶原,但其机械特性和机制作用在很大程度上尚未被探索。总的来说,我们的数据描述了apoE和apoE- hdl的一个全新的作用,它独立于血浆胆固醇水平,与细胞和组织力学生物学密切相关,并与预防动脉粥样硬化有因果关系。我们现在提出三个特定的目标来描述apoE,细胞内力,基质重塑和动脉粥样硬化保护之间的关系。在Aim 1中,我们将使用一个新的VSMC微组织微加工平台来研究胶原- viii对rho活性、收缩性、

项目成果

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Richard Assoian其他文献

Richard Assoian的其他文献

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{{ truncateString('Richard Assoian', 18)}}的其他基金

Arterial stiffening and SMC mechanobiology in Hutchinson-Guilford Progeria Syndrome
哈钦森-吉尔福德早衰综合症中的动脉硬化和 SMC 力学生物学
  • 批准号:
    10368103
  • 财政年份:
    2019
  • 资助金额:
    $ 45.79万
  • 项目类别:
Arterial stiffening and SMC mechanobiology in Hutchinson-Guilford Progeria Syndrome
哈钦森-吉尔福德早衰综合症中的动脉硬化和 SMC 力学生物学
  • 批准号:
    10609809
  • 财政年份:
    2019
  • 资助金额:
    $ 45.79万
  • 项目类别:
Arterial stiffening and SMC mechanobiology in Hutchinson-Guilford Progeria Syndrome
哈钦森-吉尔福德早衰综合症中的动脉硬化和 SMC 力学生物学
  • 批准号:
    9816369
  • 财政年份:
    2019
  • 资助金额:
    $ 45.79万
  • 项目类别:
ECM stiffness, mechanotransduction, and cell cycling
ECM 硬度、力转导和细胞循环
  • 批准号:
    9978116
  • 财政年份:
    2018
  • 资助金额:
    $ 45.79万
  • 项目类别:
ECM stiffness, mechanotransduction, and cell cycling
ECM 硬度、力转导和细胞循环
  • 批准号:
    10210426
  • 财政年份:
    2018
  • 资助金额:
    $ 45.79万
  • 项目类别:
Aging, gender and arterial stiffness in atherosclerosis
动脉粥样硬化中的衰老、性别和动脉僵硬度
  • 批准号:
    8668406
  • 财政年份:
    2014
  • 资助金额:
    $ 45.79万
  • 项目类别:
apoE, arterial biomechanics, and cardiovascular disease
apoE、动脉生物力学和心血管疾病
  • 批准号:
    8919442
  • 财政年份:
    2014
  • 资助金额:
    $ 45.79万
  • 项目类别:
apoE, arterial biomechanics, and cardiovascular disease
apoE、动脉生物力学和心血管疾病
  • 批准号:
    9081644
  • 财政年份:
    2014
  • 资助金额:
    $ 45.79万
  • 项目类别:
apoE, arterial biomechanics, and cardiovascular disease
apoE、动脉生物力学和心血管疾病
  • 批准号:
    9305135
  • 财政年份:
    2014
  • 资助金额:
    $ 45.79万
  • 项目类别:
Aging, gender and arterial stiffness in atherosclerosis
动脉粥样硬化中的衰老、性别和动脉僵硬度
  • 批准号:
    9268535
  • 财政年份:
    2014
  • 资助金额:
    $ 45.79万
  • 项目类别:

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