Immune Infiltration in Atherosclerosis is Mediated by Cuproptosis-Associated Ferroptosis Genes

IF 0.9 4区 医学 Q4 CARDIAC & CARDIOVASCULAR SYSTEMS Cardiovascular Innovations and Applications Pub Date : 2023-03-08 DOI:10.15212/cvia.2023.0003
Bo Zhang, Shuhan Li, Han Liu, Dongze Wang, Ang Gao, Yihan Wang, Zhiyuan Gao, Tongyu Hou, Qian Xu
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Abstract

Aims: In this study, we aimed to identify cuproptosis-associated ferroptosis genes in the atherosclerosis microarray of the Gene Expression Omnibus (GEO) database and to explore hub gene-mediated immune infiltration in atherosclerosis. Background: Immune infiltration plays a crucial role in atherosclerosis development. Ferroptosis is a mode of cell death caused by the iron-dependent accumulation of lipid peroxides. Cuproptosis is a recently discovered type of programmed cell death. No previous studies have examined the mechanism of cuproptosis-associated ferroptosis gene regulation in immune infiltration in atherosclerosis. Methods: We searched the qualified atherosclerosis gene microarray in the GEO database, integrated it with ferroptosis and cuproptosis genes, and calculated the correlation coefficients. We then obtained the cuproptosis-associated ferroptosis gene matrix and screened differentially expressed genes. Subsequently, we performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses and protein–protein interaction network analysis of differentially expressed genes. We also screened hub genes according to the Matthews correlation coefficient (MCC) algorithm. We conducted enrichment analysis of hub genes to explore their functions and predict related microRNAs (P<0.05). We also used the single-sample gene set enrichment analysis (ssGSEA) algorithm to analyze the relationships between hub genes and immune infiltration, and used immune-associated hub genes to construct a risk model. Finally, we used the drug prediction results and molecular docking technology to explore potential therapeutic drugs targeting the hub genes. Results: Seventy-eight cuproptosis-associated ferroptosis genes were found to be involved in the cellular response to oxidative and chemical stress, and to be enriched in multiple pathways, including ferroptosis, glutathione metabolism, and atherosclerosis. Ten hub genes were identified with the MCC algorithm; according to the ssGSEA algorithm, these genes were closely associated with immune infiltration, thus indicating that cuproptosis-associated ferroptosis genes may participate in atherosclerosis by mediating immune infiltration. The receiver operating characteristic curve indicated that the model had a good ability to predict atherosclerosis risk. The results of drug prediction (adjusted P<0.001) and molecular docking showed that glutathione may be a potential therapeutic drug that targets the hub genes. Conclusion: Cuproptosis-associated ferroptosis genes are associated with immune infiltration in atherosclerosis.
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动脉粥样硬化中的免疫浸润是由杯状细胞相关脱铁基因介导的
目的:在本研究中,我们旨在在基因表达综合数据库(GEO)的动脉粥样硬化微阵列中鉴定铜中毒相关的脱铁基因,并探索中枢基因介导的动脉粥样硬化免疫浸润。背景:免疫浸润在动脉粥样硬化的发展中起着至关重要的作用。脱铁症是一种由脂质过氧化物的铁依赖性积累引起的细胞死亡模式。杯状细胞病是最近发现的一种程序性细胞死亡。以前没有研究检测动脉粥样硬化免疫浸润中铜中毒相关脱铁基因调控的机制。方法:在GEO数据库中检索符合条件的动脉粥样硬化基因微阵列,将其与ferroptosis和Copoptosis基因整合,计算相关系数。然后,我们获得了铜中毒相关的脱铁性贫血基因基质,并筛选了差异表达的基因。随后,我们对差异表达基因进行了基因本体论和京都基因和基因组百科全书富集分析以及蛋白质-蛋白质相互作用网络分析。我们还根据Matthews相关系数(MCC)算法筛选了枢纽基因。我们对hub基因进行了富集分析,以探索其功能并预测相关的微小RNA(P<0.05)。我们还使用单样本基因集富集分析(ssGSEA)算法分析了hub基因与免疫浸润之间的关系,并使用免疫相关的hub基因构建了风险模型。最后,我们利用药物预测结果和分子对接技术,探索了针对中枢基因的潜在治疗药物。结果:发现78个铜中毒相关的脱铁基因参与细胞对氧化和化学应激的反应,并在多种途径中富集,包括脱铁、谷胱甘肽代谢和动脉粥样硬化。用MCC算法鉴定出10个枢纽基因;根据ssGSEA算法,这些基因与免疫浸润密切相关,因此表明铜中毒相关的脱铁基因可能通过介导免疫浸润参与动脉粥样硬化。受试者工作特性曲线表明,该模型具有较好的动脉粥样硬化风险预测能力。药物预测(调整后P<0.001)和分子对接的结果表明,谷胱甘肽可能是一种潜在的靶向中枢基因的治疗药物。结论:杯状细胞变性相关的脱铁基因与动脉粥样硬化的免疫浸润有关。
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来源期刊
Cardiovascular Innovations and Applications
Cardiovascular Innovations and Applications CARDIAC & CARDIOVASCULAR SYSTEMS-
CiteScore
0.80
自引率
20.00%
发文量
222
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