Peking University China-Japan Friendship School of Clinical Medicine, NO. 2 Yinghua Eastern Road, Beijing, China.
Department of Cardiovascular Surgery, China-Japan Friendship Hospital, NO. 2 Yinghua Eastern Road, Beijing, 10029, China.
Sci Rep. 2024 Jan 2;14(1):233. doi: 10.1038/s41598-023-50689-x.
Atherosclerosis is a chronic inflammatory disease characterized with innate and adaptive immunity but also involves pyroptosis. Few studies have explored the role of pyroptosis in advanced atherosclerotic plaques from different vascular beds. Here we try to identify the different underlying function of pyroptosis in the progression of atherosclerosis between carotid arteries and femoral. arteries. We extracted gene expression levels from 55 advanced carotid or femoral atherosclerotic plaques. The pyroptosis score of each sample was calculated by single-sample-gene-set enrichment analysis (ssGSEA). We then divided the samples into two clusters: high pyroptosis scores cluster (PyroptosisScoreH cluster) and low pyroptosis scores cluster (PyroptosisScoreL cluster), and assessed functional enrichment and immune cell infiltration in the two clusters. Key pyroptosis related genes were identified by the intersection between results of Cytoscape and LASSO (Least Absolute Shrinkage and Selection Operator) regression analysis. Finally, all key pyroptosis related genes were validated in vitro. We found all but one of the 29 carotid plaque samples belonged to the PyroptosisScoreH cluster and the majority (19 out of 26) of femoral plaques were part of the PyroptosisScoreL cluster. Atheromatous plaque samples in the PyroptosisScoreL cluster had higher proportions of gamma delta T cells, M2 macrophages, myeloid dendritic cells (DCs), and cytotoxic lymphocytes (CTLs), but lower proportions of endothelial cells (ECs). Immune full-activation pathways (e.g., NOD-like receptor signaling pathway and NF-kappa B signaling pathway) were highly enriched in the PyroptosisScoreH cluster. The key pyroptosis related genes GSDMD, CASP1, NLRC4, AIM2, and IL18 were upregulated in advanced carotid atherosclerotic plaques. We concluded that compared to advanced femoral atheromatous plaques, advanced carotid atheromatous plaques were of higher grade of pyroptosis. GSDMD, CASP1, NLRC4, AIM2, and IL18 were the key pyroptosis related genes, which might provide a new sight in the prevention of fatal strokes in advanced carotid atherosclerosis.
动脉粥样硬化是一种慢性炎症性疾病，其特征为先天免疫和适应性免疫，但也涉及细胞焦亡。很少有研究探讨不同血管床的晚期动脉粥样硬化斑块中细胞焦亡的作用。在这里，我们试图确定颈动脉和股动脉动脉粥样硬化进展过程中细胞焦亡的不同潜在功能。我们从 55 个晚期颈动脉或股动脉粥样硬化斑块中提取基因表达水平。通过单样本基因集富集分析（ssGSEA）计算每个样本的细胞焦亡评分。然后，我们将样本分为两个聚类：高细胞焦亡评分聚类（PyroptosisScoreH 聚类）和低细胞焦亡评分聚类（PyroptosisScoreL 聚类），并评估两个聚类中的功能富集和免疫细胞浸润。通过 Cytoscape 和 LASSO（最小绝对收缩和选择算子）回归分析结果的交集确定关键细胞焦亡相关基因。最后，在体外验证所有关键细胞焦亡相关基因。我们发现 29 个颈动脉斑块样本中除 1 个外均属于 PyroptosisScoreH 聚类，而 26 个股动脉斑块中大多数（19 个）属于 PyroptosisScoreL 聚类。细胞焦亡评分低聚类中的动脉粥样硬化斑块样本中，γδT 细胞、M2 巨噬细胞、髓样树突状细胞（DC）和细胞毒性淋巴细胞（CTL）的比例较高，而内皮细胞（EC）的比例较低。免疫全激活途径（如 NOD 样受体信号通路和 NF-κB 信号通路）在 PyroptosisScoreH 聚类中高度富集。关键细胞焦亡相关基因 GSDMD、CASP1、NLRC4、AIM2 和 IL18 在晚期颈动脉粥样硬化斑块中上调。我们得出结论，与晚期股动脉粥样硬化斑块相比，晚期颈动脉粥样硬化斑块的细胞焦亡程度更高。GSDMD、CASP1、NLRC4、AIM2 和 IL18 是关键的细胞焦亡相关基因，这可能为预防晚期颈动脉粥样硬化性致命性卒中提供新的视角。
