Role of ferroptosis-related genes in Stanford type a aortic dissection and identification of key genes: new insights from bioinformatic analysis

Zou, Hua-Xi; Qiu, Bai‐Quan; Lai, Songqing; Huang, Huang; Zhou, Xueliang; Gong, Chengwu; Wang, Lijun; Yuan, Mingming; He, An-Di; Liu, Jichun

doi:10.1080/21655979.2021.1988840

Cited by 15 publications

(12 citation statements)

References 60 publications

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“…Surprisingly, liproxstatin-1 significantly inhibited BAPN-induced elastic fiber breakage, SMC loss, AD and rupture in mice. Recently, a study demonstrated that ferroptosis may be involved in the occurrence of AD by using bioinformatics analysis [56], while our present study confirmed that ferroptosis of SMCs is an important cause of medial degeneration of the aorta and the progression of AD by conducting experiments in HASMCs, mice and specimens of patients with AD.…”

Section: Discussionsupporting

confidence: 84%

Targeting Ferroptosis as a Novel Approach to Alleviate Aortic Dissection

Li¹,

Yi²,

He³

et al. 2022

Int. J. Biol. Sci.

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A variety of programmed cell death types have been shown to participate in the loss of smooth muscle cells (SMCs) during the development of aortic dissection (AD), but it is still largely unclear whether ferroptosis is involved in the development of AD. In the present study, we found that the expression of key ferroptosis regulatory proteins, solute carrier family 7 member 11 (SLC7A11), ferroptosis suppressor protein 1 (FSP1) and glutathione peroxidase 4 (GPX4) were downregulated in aortas of Stanford type A AD (TAAD) patients, and liproxstatin-1, a specific inhibitor of ferroptosis, obviously abolished the β-aminopropionitrile (BAPN)-induced development and rupture of AD in mice. Furthermore, the expression of methyltransferase-like 3 (METTL3), a major methyltransferase of RNA m 6 A, was remarkably upregulated in the aortas of TAAD patients, and the protein levels of METTL3 were negatively correlated with SLC7A11 and FSP1 levels in human aortas. Overexpression of METTL3 in human aortic SMCs (HASMCs) inhibited, while METTL3 knockdown promoted SLC7A11 and FSP1 expression. More importantly, overexpression of METTL3 facilitated imidazole ketone erastin-and cystine deprivation-induced ferroptosis, while knockdown of METTL3 repressed ferroptosis of HASMCs. Overexpression of either SLC7A11 or FSP1 largely abrogated the effect of METTL3 on HASMC ferroptosis. Therefore, we have revealed that ferroptosis is a critical cause of AD in both humans and mice and that METTL3 promotes ferroptosis of HASMCs by inhibiting the expression of SLC7A11 and FSP1. Thus, targeting ferroptosis or m 6 A RNA methylation is a potential novel strategy for the treatment of AD.

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Section: Discussionsupporting

confidence: 84%

Targeting Ferroptosis as a Novel Approach to Alleviate Aortic Dissection

Li¹,

Yi²,

He³

et al. 2022

Int. J. Biol. Sci.

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“…Moreover, NLR Family Pyrin Domain Containing 3- (NLRP3-) caspase-1 inflammasome could directly cleave and degrade contractile proteins in VSMCs, and NLRP3 or caspase-1 deficiency in mice significantly reduced angiotensin II-induced AD formation [ 32 , 33 ], indicating that pyroptosis in VSMCs contributes to the development of TAAD. Additionally, although direct evidence regarding the role of ferroptosis in AD development is lacking, Zou et al [ 34 ], using bioinformatic analysis, demonstrated differentially expressed ferroptosis-related genes in the normal and TAAD samples. Furthermore, much of the information about necroptosis and AD development has been derived from animal experiments [ 18 , 19 ].…”

Section: Discussionmentioning

confidence: 99%

Role of Necroptosis and Immune Infiltration in Human Stanford Type A Aortic Dissection: Novel Insights from Bioinformatics Analyses

Liu

Wei

Liu

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background. Stanford type A aortic dissection (TAAD) is one of the most life-threatening cardiovascular emergencies with high mortality and morbidity, and necroptosis is a newly identified type of programmed cell death and contributes to the pathogenesis of various cardiovascular diseases. However, the role of necroptosis in TAAD has not been elucidated. This study was aimed at determining the role of necroptosis in TAAD using bioinformatics analyses. Methods. The RNA sequencing dataset GSE153434 and the microarray dataset GSE52093 were obtained from Gene Expression Omnibus (GEO) database. Differentially expressed genes of necroptosis (NRDEGs) were identified based on differentially expressed genes (DEGs) and necroptosis gene set. Gene set enrichment analysis (GSEA) was applied to evaluate the gene enrichment signaling pathway in TAAD. The STRING database and Cytoscape software were used to establish and visualize protein-protein interaction (PPI) networks and identify the key functional modules of NRDEGs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of NRDEGs were also performed. Additionally, Spearman correlations were used to construct the necroptosis-related transcription factor-target genes regulatory network, immune infiltration patterns were analyzed using the ImmuCellAI algorithm, and the correlation between immune cell-type abundance and NRDEGs expression was investigated. The expression levels of NRDEGs and immune infiltration were additionally verified in the GSE52093 dataset. Results. We found that the necroptosis pathway was considerably enriched and activated in TAAD samples. Overall, 25 NRDEGs were identified including MLKL, RIPK1, and FADD, and among them, 18 were verified in the validation set. Moreover, GO and KEGG enrichment analyses found that NRDEGs were primarily involved in the tumor necrosis factor signaling pathway, nucleotide-binding oligomerization domain-like receptor signaling pathway, and interleukin-17 signaling pathway. The imbalance of Th17/Treg cells was identified in the TAAD samples. Furthermore, correlation analysis indicated that expression of NRDEGs was positively associated with proinflammatory immune-cell infiltrations and negatively associated with anti-inflammatory or regulatory immune-cell infiltrations. Conclusions. The present findings suggest that necroptosis phenomenon exists in TAAD and correlates with immune cell infiltration, which indicate necroptosis may promote the development of TAAD through activating immune infiltration and immune response. This study paves a new road to future investigation of the pathogenic mechanisms and therapeutic strategies for TAAD.

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“…The Quantitative real-time PCR (qRT-PCR) protocol was as described in our previous study ( 28 ). Briefly, total RNA was extracted from the cells using TRIzol reagent (Invitrogen, United States), and the quality and yield of RNA were evaluated to confirm that the isolated RNA could be used to assess mRNA expression.…”

Section: Methodsmentioning

confidence: 99%

“…Exploring the molecular biology of disease based on the transcriptomes of human pathological tissues may bring the closest realistic insight, which has already been applied in various disease studies and transformed into clinical benefits ( 28 – 30 ). In this study, we analyzed the differential expression of autophagy-related genes (ARGs) in SCM based on the transcriptomes of human septic heart samples and further explored their potential crosstalk and functional pathways.…”

Section: Introductionmentioning

confidence: 99%

Dysregulated autophagy-related genes in septic cardiomyopathy: Comprehensive bioinformatics analysis based on the human transcriptomes and experimental validation

Zou

Qiu

Zhang

et al. 2022

Front. Cardiovasc. Med.

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Septic cardiomyopathy (SCM) is severe organ dysfunction caused by sepsis that is associated with poor prognosis, and its pathobiological mechanisms remain unclear. Autophagy is a biological process that has recently been focused on SCM, yet the current understanding of the role of dysregulated autophagy in the pathogenesis of SCM remains limited and uncertain. Exploring the molecular mechanisms of disease based on the transcriptomes of human pathological samples may bring the closest insights. In this study, we analyzed the differential expression of autophagy-related genes in SCM based on the transcriptomes of human septic hearts, and further explored their potential crosstalk and functional pathways. Key functional module and hub genes were identified by constructing a protein–protein interaction network. Eight key genes (CCL2, MYC, TP53, SOD2, HIF1A, CTNNB1, CAT, and ADIPOQ) that regulate autophagy in SCM were identified after validation in a lipopolysaccharide (LPS)-induced H9c2 cardiomyoblast injury model, as well as the autophagic characteristic features. Furthermore, we found that key genes were associated with abnormal immune infiltration in septic hearts and have the potential to serve as biomarkers. Finally, we predicted drugs that may play a protective role in SCM by regulating autophagy based on our results. Our study provides evidence and new insights into the role of autophagy in SCM based on human septic heart transcriptomes, which would be of great benefit to reveal the molecular pathological mechanisms and explore the diagnostic and therapeutic targets for SCM.

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Role of ferroptosis-related genes in Stanford type a aortic dissection and identification of key genes: new insights from bioinformatic analysis

Cited by 15 publications

References 60 publications

Targeting Ferroptosis as a Novel Approach to Alleviate Aortic Dissection

Targeting Ferroptosis as a Novel Approach to Alleviate Aortic Dissection

Role of Necroptosis and Immune Infiltration in Human Stanford Type A Aortic Dissection: Novel Insights from Bioinformatics Analyses

Dysregulated autophagy-related genes in septic cardiomyopathy: Comprehensive bioinformatics analysis based on the human transcriptomes and experimental validation

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