Silencing IL12p35 Promotes Angiotensin II-Mediated Abdominal Aortic Aneurysm through Activating the STAT4 Pathway

Wang, Lanlan; Hu, Chengyun; Dong, Yongfei; Dai, Feibiao; Xu, Yaping; Dai, Yong; Shao, Li-Jie; Zhu, Dawei

doi:10.1155/2021/9450843

Cited by 6 publications

(4 citation statements)

References 50 publications

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“…Wang et al recently reported that IL-12p35 regulates IL-6 through the signal transducer and activator of transcription 4 (STAT4) pathway in the inflammatory process of AAA. They also confirmed that IL-6 plays a role in inflammation in AAA (39). However, another study showed that IL-6 has a limited contribution to inflammation in AAA (37).…”

Section: Discussionmentioning

confidence: 75%

Identification of differentially expressed ferroptosis-related genes in abdominal aortic aneurysm: Bioinformatics analysis

Wang

Song²,

Li³

et al. 2022

Front. Cardiovasc. Med.

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PurposeFerroptosis plays a crucial role in the development and progression of abdominal aortic aneurysm (AAA). The aim of this study was to identify differentially expressed genes associated with ferroptosis in AAA through bioinformatics analysis combined with experimental validation.Materials and methodsFirstly, the mRNA expression profile datasets GSE57691 and GSE47472 from Gene Expression Omnibus database were screened, and principal component analysis was carried out. Next, the R software (version 4.0.0) was used to analyze potentially differentially expressed genes associated with AAA and ferroptosis. Subsequently, protein–protein interaction analysis, gene ontology enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed on the selected candidate genes. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression levels of the first five selected abnormal ferroptosis-related genes in clinical samples obtained from patients with AAA and healthy controls.ResultsBased on the information contained in the two datasets, a total of 20 differentially expressed ferroptosis-related genes (three upregulated genes and 17 downregulated genes) were selected. Protein–protein interaction analysis demonstrated interaction between these genes, while gene ontology enrichment analysis of ferroptosis genes with differential expression indicated that some enrichment items were associated with oxidative stress. The qRT-PCR results showed that the expression levels of interleukin-6 (IL-6), peroxiredoxin 1 (PRDX1), and stearoyl-CoA desaturase (SCD) were consistent with the bioinformatics prediction results obtained from the mRNA chip.ConclusionBioinformatics analysis identified 20 potential ferroptosis-related differentially expressed genes in AAA. Further verification by qRT-PCR showed that IL-6, PRXD1, and SCD might affect the process of AAA by regulating ferroptosis. Our results might assist in further understanding the pathogenesis of AAA and guiding treatment.

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Section: Discussionmentioning

confidence: 75%

Identification of differentially expressed ferroptosis-related genes in abdominal aortic aneurysm: Bioinformatics analysis

Wang

Song²,

Li³

et al. 2022

Front. Cardiovasc. Med.

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“…[ 45,46 ] In our study, an increased level of pro‐inflammatory cytokines was observed in abdominal artery segments of AAA mice, consistent with Wang's report. [ 47 ] Pirfenidone dramatically repressed the inflammation in abdominal artery segments of AAA mice, implying that pirfenidone showed a protective function on the dysfunction of the endothelium in AAA mice. Furthermore, the activated TLR4/NF‐κB signaling observed in Ang II‐treated HAECs was suppressed by pirfenidone, which further confirmed that the protective function of pirfenidone on endothelial injury might be mediated by its inhibition of NF‐κB inflammatory signaling.…”

Section: Discussionmentioning

confidence: 99%

The protective effects of pirfenidone in preventing abdominal aortic aneurysm formation

Yong,

Wang,

Song

et al. 2023

J Biochem & Molecular Tox

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Vascular endothelial growth factor (VEGF)‐mediated angiogenesis participates in the initiation and progression of abdominal aortic aneurysm (AAA). Pirfenidone is a compound that has anti‐inflammatory and antioxidant properties and suppresses angiogenesis. Pirfenidone targets the extracellular matrix (ECM) and has therapeutic effects on fibrotic diseases. Therefore, we speculated that pirfenidone might have meaningful therapeutic effects in AAA, and the current study was designed to investigate this capacity. An AAA model was constructed in mice using a long‐term injection of angiotensin II (Ang II), followed by a 28‐day administration of 200 mg/kg/day pirfenidone. Increased maximal external diameter of the abdominal artery, promoted levels of VEGF‐A and its receptor VEGF‐R2, upregulated matrix metallopeptidases (MMP)‐2 and MMP‐9, and elevated release of pro‐inflammatory cytokines were observed in AAA mice, which were extremely repressed by 200 mg/kg pirfenidone. Human aortic endothelial cells (HAECs) were stimulated with Ang II for 1 day, in the presence or absence of pirfenidone (100 nM). Elevated expression of VEGF‐A and VEGF‐R2, facilitated proliferation, increased tube formation ability, and upregulated MMP‐2 and MMP‐9 were observed in Ang II‐stimulated HAECs, all of which were significantly rescued by 100 nM pirfenidone. Finally, the elevated levels of myeloid differentiation primary response 88 and phosphorylated nuclear factor‐kappa‐B subunit p65 observed in Ang II‐stimulated HAECs were repressed by pirfenidone. Collectively, pirfenidone alleviated AAA by inhibiting ECM degradation and ameliorating endothelial dysfunction.

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“…Studies by Treska et al, Cheuk et al, and Wallinder et al demonstrated that pro-inflammatory cytokines such as IL-6, IL-8, and TNF-α were upregulated in the plasma and aneurysm tissue of patients with AAA rupture ( 41 – 43 ). STAT signaling pathways could mediate cellular activity, including the inflammatory response, and Wang et al reported that the STAT4 signaling pathway is involved in the development and rupture of AAA ( 44 ). There are also studies demonstrating that the mTOR and VEGF signaling pathways play the important roles in the development of AAA ( 45 , 46 ), but their roles in aortic rupture remain unclear.…”

Section: Discussionmentioning

confidence: 99%

“…There is an increasing number of studies suggesting that inflammation is significantly associated with aortic rupture. Aurelian et al reported that the neutrophil-to-lymphocyte ratio (NLR) was increased in patients with aortic rupture compared to patients with intact AAAs, and an NLR of > 5 indicated a fivefold increased risk of aortic rupture (40) involved in the development and rupture of AAA (44). There are also studies demonstrating that the mTOR and VEGF signaling pathways play the important roles in the development of AAA (45, 46), but their roles in aortic rupture remain unclear.…”

Section: Xgboost Model Predicted Accuracymentioning

confidence: 99%

Identification of biomarkers and analysis of infiltrated immune cells in stable and ruptured abdominal aortic aneurysms

Chen

Ouyang²,

Fang³

et al. 2022

Front. Cardiovasc. Med.

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ObjectivesThe mortality rate of abdominal aortic aneurysm (AAA) is extremely high in the older population. This study aimed to identify potential biomarkers of AAA and aortic rupture and analyze infiltration of immune cells in stable and ruptured AAA samples.MethodsRaw data of GSE47472, GSE57691, and GSE98278 were downloaded. After data processing, the co-expression gene networks were constructed. Gene Ontology and pathway enrichment analysis of AAA- and aortic rupture-related gene modules were conducted using the Database for Annotation, Visualization, and Integrated Discovery. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were used for further enrichment analysis. The CIBERSORT tool was used to analyze the relative abundance of immune cells in samples. Differentially expressed immune-related genes were analyzed between different samples. Predictive models were constructed via extreme gradient boosting, and hub genes were identified according to feature importance.ResultsBlue and yellow modules were significantly related to AAA, and genes in these modules were associated with the aortic wall and immune response, respectively. In terms of aortic rupture, the most relevant module was significantly enriched in the inflammatory response. The results of GSEA and GSVA suggested that immune cells and the inflammatory response were involved in the development of AAA and aortic rupture. There were significant differences in the infiltration of immune cells and expression levels of immune-related genes among different samples. NFKB1 might be an important transcription factor mediating the inflammatory response of AAA and aortic rupture. After the construction of a predictive model, CD19, SELL, and CCR7 were selected as hub genes for AAA whereas OAS3, IFIT1, and IFI44L were identified as hub genes for aortic rupture.ConclusionWeakening of the aortic wall and the immune response both contributed to the development of AAA, and the inflammatory response was closely associated with aortic rupture. The infiltration of immune cells was significantly different between different samples. NFKB1 might be an important transcription factor in AAA and aortic rupture. CD19, SELL, and CCR7 had potential diagnostic value for AAA. OAS3, IFIT1, and IFI44L might be predictive factors for aortic rupture.

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Silencing IL12p35 Promotes Angiotensin II-Mediated Abdominal Aortic Aneurysm through Activating the STAT4 Pathway

Cited by 6 publications

References 50 publications

Identification of differentially expressed ferroptosis-related genes in abdominal aortic aneurysm: Bioinformatics analysis

Identification of differentially expressed ferroptosis-related genes in abdominal aortic aneurysm: Bioinformatics analysis

The protective effects of pirfenidone in preventing abdominal aortic aneurysm formation

Identification of biomarkers and analysis of infiltrated immune cells in stable and ruptured abdominal aortic aneurysms

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