Novel genetic Insight into the molecular pathogenesis of atherosclerosis

动脉粥样硬化分子发病机制的新遗传学见解

基本信息

项目摘要

Atherosclerosis is a chronic inflammatory condition characterized by arterial plaques composed of cholesterol- filled macrophages, a necrotic lipid core, and a fibrous cap containing vascular smooth muscle cells (SMCs). Extensive work has defined how genetic variants altering lipid levels and inflammation contribute to atherosclerosis, but less is known as to how genetic alterations affecting SMCs predispose to atherosclerosis. An expanded role for SMCs in atherosclerotic lesions is evoked by the finding that SMCs in plaques lose SMC differentiation markers and initiate expression of macrophage markers, thus becoming a macrophage-like cell. Similarly, SMCs downregulate SMC markers in vitro, but upregulate macrophage markers with exposure to free cholesterol. We determined that some heterozygous missense mutations in ACTA2, which encodes the SMC-specific isoform of α-actin, predispose individuals to both thoracic aortic disease and early onset coronary artery disease (CAD). We have engineered a mouse model with one such mutation and SMCs explanted from Acta2R149C/+ aortas de-differentiate and increase expression of macrophage markers at much lower concentrations of free cholesterol than wildtype SMCs. Furthermore, when the Acta2R149C/+ mice are crossed into Apoe-/- mice and fed a high fat diet, the double mutant mice have a significantly increased burden of atherosclerotic plaques when compared to similarly treated Apoe-/- mice. We hypothesize that early onset CAD associated with the SM α-actin R149C mutation is due to disrupted folding of the mutant actin, leading to increased Klf4 activation and augmented SMC phenotypic switching to macrophage-like cells. We further speculate that, although many ACTA2 mutations may increase SMC proliferation and migration, only variants that increase SMC switching to macrophage-like cells will predispose to early onset CAD. The aims to address these hypotheses are the following: (1) Characterize the atherosclerotic lesions in the Acta2R149C/+ mice, including identifying the origin of the SMCs and macrophages in the lesions; (2) Identify cellular pathways responsible for enhanced Acta2R149C/+ SMC switching to a macrophage-like cell with exposure to cholesterol, and assess the role of these pathways in the increased plaque burden in Acta2R149C/+ mice through genetic manipulation. (3) Determine how CAD-associated ACTA2 mutations disrupt folding by the chaperonin CCT complex, and show causality between SM α-actin folding defects and CAD-predisposing ACTA2 missense mutations. Thus, the proposed research will provide valuable new insights into the role of SMC phenotypic switching as a risk factor for atherosclerosis, and may also identify novel therapeutic targets that can delay or even prevent disease progression.
动脉粥样硬化是一种以动脉斑块为特征的慢性炎症

项目成果

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DIANNA M MILEWICZ其他文献

DIANNA M MILEWICZ的其他文献

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{{ truncateString('DIANNA M MILEWICZ', 18)}}的其他基金

2023 Elastin, Elastic Fibers and Microfibrils Gordon Research Conference and Gordon Research Seminar
2023年弹性蛋白、弹性纤维和微纤维戈登研究会议和戈登研究研讨会
  • 批准号:
    10754079
  • 财政年份:
    2023
  • 资助金额:
    $ 64.03万
  • 项目类别:
Medical Scientist Training Program
医学科学家培训计划
  • 批准号:
    10715841
  • 财政年份:
    2023
  • 资助金额:
    $ 64.03万
  • 项目类别:
Novel genetic Insight into the molecular pathogenesis of atherosclerosis
动脉粥样硬化分子发病机制的新遗传学见解
  • 批准号:
    10360600
  • 财政年份:
    2019
  • 资助金额:
    $ 64.03万
  • 项目类别:
Novel genetic Insight into the molecular pathogenesis of atherosclerosis
动脉粥样硬化分子发病机制的新遗传学见解
  • 批准号:
    10116456
  • 财政年份:
    2019
  • 资助金额:
    $ 64.03万
  • 项目类别:
UTHealth/MDACC MSTP Alumni Mentoring Program
UTHealth/MDACC MSTP 校友辅导计划
  • 批准号:
    10394050
  • 财政年份:
    2018
  • 资助金额:
    $ 64.03万
  • 项目类别:
Medical Scientist Training Program
医学科学家培训计划
  • 批准号:
    10409702
  • 财政年份:
    2018
  • 资助金额:
    $ 64.03万
  • 项目类别:
Medical Scientist Training Program
医学科学家培训计划
  • 批准号:
    9924573
  • 财政年份:
    2018
  • 资助金额:
    $ 64.03万
  • 项目类别:
Medical Scientist Training Program
医学科学家培训计划
  • 批准号:
    10158495
  • 财政年份:
    2018
  • 资助金额:
    $ 64.03万
  • 项目类别:
Mutations in Smooth Muscle Contractile Proteins: Pathways to Vascular Diseases
平滑肌收缩蛋白突变:血管疾病的途径
  • 批准号:
    8898184
  • 财政年份:
    2012
  • 资助金额:
    $ 64.03万
  • 项目类别:
Genetic Predisposition To Thoracic Aortic Aneurysms/Dissections
胸主动脉瘤/夹层的遗传倾向
  • 批准号:
    8828767
  • 财政年份:
    2012
  • 资助金额:
    $ 64.03万
  • 项目类别:

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