Lamin A/C Expression in Hematopoietic Cells Declines During Human Aging and Constrains Atherosclerosis in Mice.

IF 7.4 1区 医学 Q1 HEMATOLOGY
Marta Amorós-Pérez, Alberto Del Monte-Monge, Pilar Gonzalo, María J Andrés-Manzano, Cristina Rius, Víctor Fanjul, Cristina González-Gómez, Guillermo Moreno, Alberto Benguria, Ana Dopazo, Fátima Sanchez-Cabo, Carlos Torroja, Fernando Martínez de Benito, Bianca Calì, Pablo Vargas, Carlos Silvestre-Roig, José M González-Granado, Héctor Bueno, José J Fuster, Vicente Andrés
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引用次数: 0

Abstract

Background: Aging is the primary risk factor for atherosclerosis, a degenerative process regulated by immune cells and the leading cause of death worldwide. Previous studies on premature aging syndromes have linked atherosclerosis to defects in A-type lamins, key nuclear envelope components. However, whether these defects influence atherosclerosis during normal aging remains unexplored. Here, we examined how aging affects lamin A/C expression in circulating leukocytes and investigated the impact of manipulating their expression in hematopoietic cells on their function and atherosclerosis progression.

Methods: Flow cytometry assessed lamin A/C expression in human circulating leukocytes. Bone marrow from donor mice was transplanted into lethally irradiated, Ldlr-/--deficient mice to study leukocyte extravasation into the vessel wall via intravital microscopy in the cremaster muscle, and high-fat-diet-induced atherosclerosis via Oil Red O staining of the aorta and carotid arteries. Single-cell RNA sequencing of the aorta was conducted to identify transcriptional changes associated with hematopoietic cell lamin A/C gain-of-function or loss-of-function.

Results: Human aging is associated with lower levels of lamin A/C expression in blood-borne leukocytes. To evaluate the functional relationship between hematopoietic lamin A/C expression and atherosclerosis development, we used Lmna-null mice and Lmnatg mice, the latter being the first in vivo model of lamin A gain-of-function. Transplanting lamin A/C-deficient bone marrow into Ldlr-/- mice increased leukocyte extravasation into the vessel wall and accelerated atherosclerosis. Conversely, transplantation of bone marrow overexpressing lamin A into Ldlr-/- receptor mice reduced leukocyte extravasation and atherosclerosis. Single-cell RNA sequencing of atherosclerotic mouse aorta revealed that alterations to hematopoietic cell lamin A/C expression primarily modify the transcriptome of immune cell populations and endothelial cells, affecting their functionality.

Conclusions: We suggest that the age-related decline in lamin A/C expression in blood-borne immune cells contributes to increased leukocyte extravasation and atherosclerosis, highlighting lamin A/C as a novel regulator of age-related atherosclerosis.

人衰老过程中造血细胞Lamin A/C表达下降并抑制小鼠动脉粥样硬化
背景:衰老是动脉粥样硬化的主要危险因素,这是一种由免疫细胞调节的退行性过程,也是世界范围内死亡的主要原因。先前关于早衰综合征的研究将动脉粥样硬化与a型层粘连蛋白缺陷联系起来,a型层粘连蛋白是关键的核膜成分。然而,这些缺陷是否会影响正常衰老过程中的动脉粥样硬化仍未研究。在这里,我们研究了衰老如何影响循环白细胞中纤层蛋白A/C的表达,并研究了操纵造血细胞中纤层蛋白A/C的表达对其功能和动脉粥样硬化进展的影响。方法:用流式细胞术检测人循环白细胞中lamin A/C的表达。将供体小鼠的骨髓移植到经致死性照射的Ldlr-/-缺陷小鼠体内,通过活体显微镜观察颈肌的白细胞外渗到血管壁上,并通过主动脉和颈动脉的油红O染色研究高脂肪饮食诱导的动脉粥样硬化。对主动脉进行单细胞RNA测序,以确定与造血细胞层粘连蛋白A/C功能获得或功能丧失相关的转录变化。结果:人类衰老与血源性白细胞中lamin A/C表达水平降低有关。为了评估造血层粘连蛋白A/C表达与动脉粥样硬化发展之间的功能关系,我们使用了Lmna-null小鼠和Lmnatg小鼠,后者是第一个层粘连蛋白A功能获得的体内模型。将缺乏层粘连蛋白A/ c的骨髓移植到Ldlr-/-小鼠体内会增加白细胞向血管壁外渗,加速动脉粥样硬化。相反,将过表达lamin A的骨髓移植到Ldlr-/-受体小鼠体内,可减少白细胞外渗和动脉粥样硬化。动脉粥样硬化小鼠主动脉单细胞RNA测序显示,造血细胞层粘胶蛋白A/C表达的改变主要改变免疫细胞群和内皮细胞的转录组,影响其功能。结论:我们认为,血源性免疫细胞中lamin A/C表达的年龄相关性下降有助于白细胞外渗和动脉粥样硬化的增加,强调lamin A/C是年龄相关性动脉粥样硬化的新调节剂。
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来源期刊
CiteScore
15.60
自引率
2.30%
发文量
337
审稿时长
2-4 weeks
期刊介绍: The journal "Arteriosclerosis, Thrombosis, and Vascular Biology" (ATVB) is a scientific publication that focuses on the fields of vascular biology, atherosclerosis, and thrombosis. It is a peer-reviewed journal that publishes original research articles, reviews, and other scholarly content related to these areas. The journal is published by the American Heart Association (AHA) and the American Stroke Association (ASA). The journal was published bi-monthly until January 1992, after which it transitioned to a monthly publication schedule. The journal is aimed at a professional audience, including academic cardiologists, vascular biologists, physiologists, pharmacologists and hematologists.
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