Investigation of the molecular mechanisms of vascular endothelial dysfunction in Hutchinson-Gilford Progeria Syndrome through in vitro 2D and 3D models

通过体外2D和3D模型研究Hutchinson-Gilford早衰综合症血管内皮功能障碍的分子机制

基本信息

  • 批准号:
    10321677
  • 负责人:
  • 金额:
    $ 7.16万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-01-01 至 2022-12-31
  • 项目状态:
    已结题

项目摘要

Abstract Hutchinson-Gilford progeria syndrome (HGPS) is a rare, genetic disorder with features of accelerated aging. The majority of HGPS cases caused by a de novo point mutation in the LMNA gene (c.1824C > T; p.G608G) that results in progerin, a toxic lamin A protein variant. Children with the disease mostly die from coronary artery diseases or strokes at an average age of 14.6 years. Endothelial dysfunction is a key contributor to the cardiovascular pathobiology as the endothelium maintains vascular homeostasis and vascular tone by activating eNOS responsible for nitric oxide (NO) production. Perturbation of eNOS activity causes many diseases including atherosclerosis. Despite the vast knowledge of endothelial dysfunction in the pathogenesis of cardiovascular disease, very little known about the role of progerin in the disruption of endothelial cell function in HGPS. Furthermore, there is accumulated evidence about the role of progerin in many aspects of generalized aging and cardiovascular health. Particularly, the atherosclerotic plaques in HGPS are similar to those found in aging individuals. Moreover, vascular stiffening in HGPS is much like that seen on normal aging that manifested in both populations by increased pulse wave velocity. Using human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs), I demonstrated the reduction of endothelial nitric oxide synthase (eNOS) expression level and activity in HGPS ECs compared to their normal controls. Consequently, the depletion of nitric oxide bioavailability in HGPS ECs both in static and fluidic culture conditions. Remarkably, iPSC-derived HGPS ECs exhibited eNOS dependent functional defects in forming microvascular networks that validated through over-expression of progerin in healthy human umbilical vein endothelial cells (HUVECs). I also found that Adenine Base Editor (ABEmax) that mediates the conversion of A×T to G×C in genomic DNA efficiently corrected the HGPS mutation, and the progerin expression was significantly reduced to the basal level. In addition, ABEmax rescued the nuclear blebbing phenotype of the HGPS iPSC-ECs. Thus, the study provides valuable insights into HGPS cardiovascular pathology and cardiovascular diseases associated with normal aging, and may lead to novel strategies to treat cardiovascular disease in HGPS.
摘要 Hutchinson-Gilford早衰综合征(HGPS)是一种罕见的遗传性疾病, 加速老化大多数HGPS病例由LMNA中的从头点突变引起 基因(c.1824C > T; p.G608G),其导致早老蛋白,一种毒性核纤层蛋白A蛋白变体。儿童 大多数患有这种疾病的人死于冠状动脉疾病或中风,平均年龄为14.6岁。 年内皮功能障碍是心血管病理学的关键因素, 内皮细胞通过激活eNOS来维持血管稳态和血管张力 一氧化氮(NO)的产生。eNOS活性的扰动导致许多疾病,包括 动脉粥样硬化尽管内皮功能障碍在血管内皮细胞损伤的发病机制中有着广泛的知识, 在心血管疾病中,关于早老蛋白在破坏内皮细胞中的作用知之甚少。 HGPS中的细胞功能。此外,有积累的证据表明,早老蛋白的作用, 广义衰老和心血管健康的许多方面。特别是动脉粥样硬化 HGPS中的斑块与在老年个体中发现的斑块相似。此外, HGPS很像正常衰老,在两个人群中表现为增加 脉搏波速度 使用人诱导多能干细胞衍生的内皮细胞(iPSC-ECs),我证明了 内皮型一氧化氮合酶(eNOS)表达水平和活性降低 与正常对照相比。因此,一氧化氮生物利用度的消耗 在静态和流体培养条件下的HGPS EC中。值得注意的是,iPSC衍生的HGPS EC 在形成微血管网络方面表现出eNOS依赖性功能缺陷, 通过在健康人脐静脉内皮细胞(HUVEC)中过表达早老蛋白。 我还发现,介导A×T转化为G×C的腺嘌呤碱基编辑器(ABEmax)在 基因组DNA有效地纠正了HGPS突变, 显著降低到基础水平。此外,ABEmax挽救了核起泡 HGPS iPSC-EC的表型。因此,该研究为HGPS提供了有价值的见解 与正常衰老相关的心血管病理学和心血管疾病, 从而导致治疗HGPS心血管疾病的新策略。

项目成果

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