全基因组搜索将衰老相关分泌蛋白与小鼠和人类冠状动脉疾病的易感性联系起来。

Yuan-Zheng Zhu, Jian-Kun Liu, Xue-Er Li, Zhen-Ping Yu, Lu-Qin Yang, Qin Wan, Ya Zhao, Muhammad Saeed, An-Dong Wu, Xiao-Li Tian
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引用次数: 0

摘要

高龄是冠状动脉疾病(CAD)的一个独立风险因素,而冠状动脉疾病是导致全球死亡的主要原因。动脉粥样硬化斑块中的衰老血管细胞表现出衰老相关分泌表型(SASP)。然而,SASP 如何导致动脉粥样硬化和冠状动脉粥样硬化仍不清楚。在这里,我们整合了衰老的人冠状动脉内皮细胞(HCAECs)和主动脉平滑肌细胞(HASMCs)的 RNA 阵列数据集以及 CAD 的全基因组关联数据。在内部数据集和已发表的数据集中,我们从 HCAECs 和 HASMCs 中分别发现了 26 个和 6 个与 SASP 和 CAD 相关的基因。其中,我们发现胱抑素 C(CST3)是一种 CAD 易感基因,在 HCAECs 和 HASMCs 中均有表达,因此将其列为进一步研究的重点。我们发现它在衰老血管细胞、老化动脉和早期动脉粥样硬化中明显升高。体外实验表明,CST3 能增强单核细胞与内皮细胞的粘附。此外,配体-受体配对分析显示,COL4A1-ITGA1 和 LPL-LRP1 这两条重要通路与动脉粥样硬化发生发展的关键过程有关,包括细胞粘附、炎症反应、细胞外基质组织和脂质代谢。我们进一步证实,在敲除 COL4A1 或 ITGA1 后,单核细胞-内皮细胞粘附性降低,而在老龄小鼠和载脂蛋白E-/-小鼠的动脉内膜中,COL4A1、ITGA1 和 LPL 的表达显著增加。我们的研究结果表明,血管细胞衍生的 SASP 蛋白增加了对 CAD 的易感性,并确定了 CST3 对动脉粥样硬化的功能性贡献。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Genome-Wide Search Links Senescence-Associated Secretory Proteins With Susceptibility for Coronary Artery Disease in Mouse and Human.

Advanced age is an independent risk factor for coronary artery disease (CAD), the leading global cause of mortality. Senescent vascular cells in the atherosclerotic plaques exhibit senescence-associated secretory phenotype (SASP). How SASP contributes to atherosclerosis and CAD, however, remains unclear. Here, we integrated RNA-array datasets of senescent human coronary arterial endothelial cells (HCAECs) and aortic smooth muscle cells (HASMCs) as well as genome-wide association data for CAD. We identified 26 genes from HCAECs and 6 genes from HASMCs related to SASP and CAD in both in-house and published datasets. Of which, Cystatin C (CST3), a CAD susceptibility gene, was found to be expressed in both HCAECs and HASMCs, thus, it was prioritized for further investigation. We demonstrated it was significantly elevated in senescent vascular cells, aged arteries, and early atherosclerosis. In vitro experiments showed that CST3 enhances the monocyte-endothelial cell adhesion. Additionally, ligand-receptor pairing analyses revealed two important pathways, COL4A1-ITGA1 and LPL-LRP1 pathways, linked to the critical processes in the development of atherosclerosis, including cell adhesion, inflammation response, extracellular matrix organization, and lipid metabolism. We further demonstrated a reduced monocyte-endothelial cell adhesion following the knockdown of COL4A1 or ITGA1 and a significantly increased expression of COL4A1, ITGA1, and LPL in arterial intima of aged mice and ApoE-/- mice. Our findings demonstrate that vascular cell-derived SASP proteins increase the CAD susceptibility and identify CST3 functionally contributing to atherosclerosis.

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