揭示新型冠状病毒肺炎患者心脏中严重急性呼吸综合征冠状病毒2感染与铁死亡的相关性。

Unraveling the relevance of SARS-Cov-2 infection and ferroptosis within the heart of COVID-19 patients.

作者信息

Alizadeh Saghati Amin, Sharifi Zahra, Hatamikhah Mehdi, Salimi Marieh, Talkhabi Mahmood

机构信息

Department of Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran.

Department of Animal Sciences and Marine Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran.

出版信息

Heliyon. 2024 Aug 24;10(17):e36567. doi: 10.1016/j.heliyon.2024.e36567. eCollection 2024 Sep 15.

BACKGROUND

The coronavirus disease 2019 (COVID-19) was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which led to a huge mortality rate and imposed significant costs on the health system, causing severe damage to the cells of different organs such as the heart. However, the exact details and mechanisms behind this damage are not clarified. Therefore, we aimed to identify the cell and molecular mechanism behind the heart damage caused by SARS-Cov-2 infection.

METHODS

RNA-seq data for COVID-19 patients' hearts was analyzed to obtain differentially expressed genes (DEGs) and differentially expressed ferroptosis-related genes (DEFRGs). Then, DEFRGs were used for analyzing GO and KEGG enrichment, and perdition of metabolites and drugs. we also constructed a PPI network and identified hub genes and functional modules for the DEFRGs. Subsequently, the hub genes were validated using two independent RNA-seq datasets. Finally, the miRNA-gene interaction networks were predicted in addition to a miRNA-TF co-regulatory network, and important miRNAs and transcription factors (TFs) were highlighted.

FINDINGS

We found ferroptosis transcriptomic alterations within the hearts of COVID-19 patients. The enrichment analyses suggested the involvement of DEFRGs in the citrate cycle pathway, ferroptosis, carbon metabolism, amino acid biosynthesis, and response to oxidative stress. IL6, CDH1, AR, EGR1, SIRT3, GPT2, VDR, PCK2, VDR, and MUC1 were identified as the ferroptosis-related hub genes. The important miRNAs and TFs were miR-124-3P, miR-26b-5p, miR-183-5p, miR-34a-5p and miR-155-5p; EGR1, AR, IL6, HNF4A, SRC, EZH2, PPARA, and VDR.

CONCLUSION

These results provide a useful context and a cellular snapshot of how ferroptosis affects cardiomyocytes (CMs) in COVID-19 patients' hearts. Besides, suppressing ferroptosis seems to be a beneficial therapeutic approach to mitigate heart damage in COVID-19.

背景

2019冠状病毒病（COVID-19）由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起，导致了极高的死亡率，并给卫生系统带来了巨大成本，对心脏等不同器官的细胞造成了严重损害。然而，这种损害背后的确切细节和机制尚不清楚。因此，我们旨在确定SARS-CoV-2感染导致心脏损害背后的细胞和分子机制。

方法

分析COVID-19患者心脏的RNA测序数据，以获得差异表达基因（DEG）和差异表达铁死亡相关基因（DEFRG）。然后，使用DEFRG进行基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析，以及代谢物和药物预测。我们还构建了蛋白质-蛋白质相互作用（PPI）网络，并确定了DEFRG的枢纽基因和功能模块。随后，使用两个独立的RNA测序数据集对枢纽基因进行验证。最后，除了预测miRNA-转录因子（TF）共调控网络外，还预测了miRNA-基因相互作用网络，并突出显示了重要的miRNA和转录因子（TF）。

研究结果

我们发现COVID-19患者心脏内存在铁死亡转录组改变。富集分析表明，DEFRG参与柠檬酸循环途径、铁死亡、碳代谢、氨基酸生物合成以及对氧化应激的反应。白细胞介素6（IL6）、钙黏蛋白1（CDH1）、雄激素受体（AR）、早期生长反应蛋白1（EGR1）、沉默调节蛋白3（SIRT3）、谷丙转氨酶2（GPT2）、维生素D受体（VDR）、磷酸烯醇式丙酮酸羧激酶2（PCK2）、VDR和黏蛋白1（MUC1）被确定为铁死亡相关的枢纽基因。重要的miRNA和TF分别为miR-124-3P、miR-26b-5p、miR-183-5p、miR-34a-5p和miR-155-5p；EGR1、AR、IL6、肝细胞核因子4α（HNF4A）、原癌基因酪氨酸蛋白激酶（SRC）、增强子结合蛋白2（EZH2）、过氧化物酶体增殖物激活受体α（PPARA）和VDR。