Progerin-expressing endothelial cells are unable to adapt to shear stress
Progerin-expressing endothelial cells are unable to adapt to shear stress
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DOI：
10.1016/j.bpj.2022.01.004
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发表时间：
2022-02-15
影响因子：
3.4
通讯作者：
Conway, Daniel E.
中科院分区：
文献类型：
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作者：
Danielsson, Brooke E.;Peters, Hannah C.;Conway, Daniel E.
Hutchinson-Gilford早老综合征（HGPS）是一种罕见的早衰性疾病，由核纤层蛋白A基因的单点突变引起，导致核纤层蛋白A的截短和法尼基化形式。这种突变的核纤层蛋白A蛋白，称为pro-gerin，在核纤层的外围积累，导致异常的核形态和核硬化。患有HGPS的患者经历动脉粥样硬化的快速发作，在青少年时死于心脏病发作或中风。早老蛋白的表达已被证明会导致血管平滑肌细胞和内皮细胞（EC）的功能障碍。在这项研究中，我们研究了表达早老蛋白的内皮细胞如何适应流体剪切力，这是血流的主要机械力。我们比较了表达早老蛋白、过表达野生型核纤层蛋白A和对照内皮细胞对生理水平流体剪切应力的反应。此外，我们还敲低了内皮细胞中的ZMPSTE 24，这导致核纤层蛋白A的法尼基化增加和与HGPS相似的表型。我们的研究结果表明，无论是过度表达progerin还是ZMPSTE 24敲低的内皮细胞都不能适应剪切应力，在较长的剪切应力暴露时间（3天）内经历显著的细胞损失。过度表达野生型核纤层蛋白A的内皮细胞在适应剪切应力方面也表现出类似的损伤，包括类似水平的细胞损失。细胞核形态定量显示，在静态和剪切条件下，表达早老蛋白的内皮细胞具有相似的核异常。用洛那法尼和甲基司他（先前显示可改善HGPS核形态的药物）处理早老蛋白表达细胞和ZMPSTE 24 KD细胞，导致对剪切应力的适应性改善。此外，在早老蛋白表达之前细胞对剪切应力的预对准防止了细胞损失。我们的研究结果表明，核纤层蛋白的变化可以影响内皮细胞的能力，以适当地适应剪切应力。
Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disease caused by a single-point mu-tation in the lamin A gene, resulting in a truncated and farnesylated form of lamin A. This mutant lamin A protein, known as pro-gerin, accumulates at the periphery of the nuclear lamina, resulting in both an abnormal nuclear morphology and nuclear stiffening. Patients with HGPS experience rapid onset of atherosclerosis, with death from heart attack or stroke as teenagers. Progerin expression has been shown to cause dysfunction in both vascular smooth muscle cells and endothelial cells (ECs). In this study, we examined how progerin-expressing endothelial cells adapt to fluid shear stress, the principal mechanical force from blood flow. We compared the response to shear stress for progerin-expressing, wild-type lamin A overexpressing, and con-trol endothelial cells to physiological levels of fluid shear stress. Additionally, we also knocked down ZMPSTE24 in endothelial cells, which results in increased farnesylation of lamin A and similar phenotypes to HGPS. Our results showed that endothelial cells either overexpressing progerin or with ZMPSTE24 knockdown were unable to adapt to shear stress, experiencing signif-icant cell loss at a longer duration of exposure to shear stress (3 days). Endothelial cells overexpressing wild-type lamin A also exhibited similar impairments in adaptation to shear stress, including similar levels of cell loss. Quantification of nuclear morphology showed that progerin-expressing endothelial cells had similar nuclear abnormalities in both static and shear condi-tions. Treatment of progerin-expressing cells and ZMPSTE24 KD cells with lonafarnib and methystat, drugs previously shown to improve HGPS nuclear morphology, resulted in improvements in adaptation to shear stress. Additionally, the prealignment of cells to shear stress before progerin-expression prevented cell loss. Our results demonstrate that changes in nuclear lamins can affect the ability of endothelial cells to properly adapt to shear stress.