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.

中文翻译：

---

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

高龄是冠心病（CAD）的独立危险因素，而冠心病是全球主要的死亡原因。动脉粥样硬化斑块中的衰老血管细胞表现出衰老相关的分泌表型（SASP）。然而，SASP 如何导致动脉粥样硬化和 CAD，目前尚不清楚。在这里，我们整合了衰老人冠状动脉内皮细胞 (HCAEC) 和主动脉平滑肌细胞 (HASMC) 的 RNA 阵列数据集以及 CAD 的全基因组关联数据。我们在内部和发布的数据集中鉴定了与 SASP 和 CAD 相关的 HCAEC 中的 26 个基因和 HASMC 中的 6 个基因。其中，CAD易感基因胱抑素C（CST3）在HCAEC和HASMC中均表达，因此优先进行进一步研究。我们证明它在衰老血管细胞、老化动脉和早期动脉粥样硬化中显着升高。体外实验表明，CST3 增强单核细胞与内皮细胞的粘附。此外，配体-受体配对分析揭示了两条重要途径，COL4A1-ITGA1和LPL-LRP1途径，与动脉粥样硬化发展的关键过程相关，包括细胞粘附、炎症反应、细胞外基质组织和脂质代谢。我们进一步证明，在老年小鼠和 ApoE-/- 小鼠的动脉内膜中敲低 COL4A1 或 ITGA1 后，单核细胞-内皮细胞粘附减少，并且 COL4A1、ITGA1 和 LPL 的表达显着增加。我们的研究结果表明，血管细胞衍生的 SASP 蛋白会增加 CAD 易感性，并确定 CST3 在功能上有助于动脉粥样硬化。