ADAM10 promotes the proliferation of ligamentum flavum cells by activating the PI3K/AKT pathway

Pan, Bin; Huo, Tianqun; Cao, Menghan; Li, Jing; Luo, Xuanxiang; Qu, Zhe; Hu, Feng; Yuan, Feng; Guo, Kaijin

doi:10.3892/ijmm.2020.4809

Cited by 7 publications

(6 citation statements)

References 48 publications

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“…Our integrated analyses identified the key pathways in patients with PAH, including cAMP, ECM-receptor interaction, AMPK, hypoxia-inducible factor 1- α , and the PI3K-Akt signaling pathways [ 33 ]. The activated PI3K-Akt signaling pathways can promote the proliferation of ligamentum flavum cells [ 34 ]; mechanistically, it may lead to the proliferation of pulmonary smooth cells in PAH.…”

Section: Discussionmentioning

confidence: 99%

Single-Cell RNA-Sequencing Reveals the Active Involvement of Macrophage Polarizations in Pulmonary Hypertension

Mao

Yang

et al. 2022

Disease Markers

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Background. Sustained hypoxia can trigger a progressive rise in pulmonary artery pressure and cause serious pulmonary diseases. Macrophages play important roles along the progression of pulmonary hypertension. However, the state of macrophage polarization during the early stage of pulmonary hypertension is unclear. Methods. Unlike traditional sequencing method, single-cell sequencing can accurately distinguish among cell types and better understand cell-to-cell relationships. In this study, we investigated the polarization of macrophages in pulmonary hypertension via single-cell RNA-sequencing in a mice hypoxia model, which was then validated in patients with pulmonary hypertension. Results. We identified that the intermittent exposure to hypoxic conditions could lead to the production of more M2-type macrophages than M1-type macrophages in a mouse model. Further validation analysis was performed by analyzing lung tissue of patients with pulmonary hypertension, revealing that the number of disease-associated M2 macrophages was substantially increased. Conclusions. In this study, the active anti-inflammatory response of macrophage involved in pulmonary hypertension has been identified, suggesting that intervention against the polarization of macrophages to the M2 type may be a potential way to reduce chronic pulmonary inflammation, pulmonary vascular remodeling, and artery pressure. Thus, investigation of macrophage polarization associated with hypoxia could help us better understand disease mechanism and craft effective prevention strategies and approaches.

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Section: Discussionmentioning

confidence: 99%

Single-Cell RNA-Sequencing Reveals the Active Involvement of Macrophage Polarizations in Pulmonary Hypertension

Mao

Yang

et al. 2022

Disease Markers

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“…Both GO and KEGG analysis revealed that DEGs associated with LFH were particularly enriched in cytokine activity-related and PI3K-Akt signaling pathways. By activating the PI3K/Akt pathway, the metalloproteinase ADAM10 has been shown to increase cell proliferation and hypertrophy in LF cells in vitro ( Pan et al, 2021 ). Previous research demonstrated that inflammatory responses initiate the PI3K/Akt signaling pathway, ( He et al, 2020 ) which is an important signaling pathway for cell survival ( He et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…Ligamentum flavum hypertrophy (LFH) is a major cause of spinal stenosis, a disorder that causes sensory and motor dysfunction in the upper and lower limbs due to compression of the spinal cord and spinal nerve roots or cauda equine syndrome ( Pan et al, 2021 ). The common symptoms of limb numbness in LFH are caused by the abnormal compression of spinal nerves.…”

Section: Introductionmentioning

confidence: 99%

Immune cell infiltration and the genes associated with ligamentum flavum hypertrophy: Identification and validation

Duan

Zhao

et al. 2022

Front. Cell Dev. Biol.

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Ligamentum flavum hypertrophy (LFH) is a common cause of spinal stenosis. The aim of the current study was to identify the differentially expressed genes (DEGs) in LFH and the molecular mechanisms underlying the development of and immune responses to LFH. The gene expression omnibus (GEO) database was used to obtain the GSE113212 dataset, and the DEGs were derived from microarray data. To identify critical genes and signaling pathways, gene ontology enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein-protein interaction (PPI) network analyses were performed, followed by immune cell infiltration and Friends analyses using the retrieved datasets. The results were validated using quantitative real-time PCR. The 1530 DEGs identified comprised 971 upregulated and 559 downregulated genes. KEGG analysis revealed that DEGs were mostly enriched in the PI3K-Akt signaling pathway, while PPI network analysis identified tumor necrosis factor, interleukin (IL)-6, IL-10, epidermal growth factor receptor, and leptin as important nodes, which was validated by qPCR and IHC in human LFH tissues in vitro. A significant positive correlation was found between key LFH immune-related DEGs and several immune cell types, including T and B cells. The findings of the present study might lead to novel therapeutic targets and clinical approaches, as they provide insights into the molecular mechanisms of LFH.

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“…Multiple signaling pathways obtained through KEGG analysis and GSVA have been proven to be related to autophagy, such as the PI3K-AKT, FoxO, AMPK, MAPK and mTOR signaling pathways ( 36 ). Furthermore, LFH has been reported to be associated with several KEGG pathways, such as the PI3K-AKT, MAPK, and mTOR signaling pathways ( 37 – 39 ).…”

Section: Discussionmentioning

confidence: 99%

Revealing the novel autophagy-related genes for ligamentum flavum hypertrophy in patients and mice model

Fei¹,

Chen²,

Chen³

et al. 2022

Front. Immunol.

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BackgroundFibrosis is a core pathological factor of ligamentum flavum hypertrophy (LFH) resulting in degenerative lumbar spinal stenosis. Autophagy plays a vital role in multi-organ fibrosis. However, autophagy has not been reported to be involved in the pathogenesis of LFH.MethodsThe LFH microarray data set GSE113212, derived from Gene Expression Omnibus, was analyzed to obtain differentially expressed genes (DEGs). Potential autophagy-related genes (ARGs) were obtained with the human autophagy regulator database. Functional analyses including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, Gene Set Enrichment Analysis (GSEA), and Gene Set Variation Analysis (GSVA) were conducted to elucidate the underlying biological pathways of autophagy regulating LFH. Protein-protein interaction (PPI) network analyses was used to obtain hub ARGs. Using transmission electron microscopy, quantitative RT-PCR, Western blotting, and immunohistochemistry, we identified six hub ARGs in clinical specimens and bipedal standing (BS) mouse model.ResultsA total of 70 potential differentially expressed ARGs were screened, including 50 up-regulated and 20 down-regulated genes. According to GO enrichment and KEGG analyses, differentially expressed ARGs were mainly enriched in autophagy-related enrichment terms and signaling pathways related to autophagy. GSEA and GSVA results revealed the potential mechanisms by demonstrating the signaling pathways and biological processes closely related to LFH. Based on PPI network analysis, 14 hub ARGs were identified. Using transmission electron microscopy, we observed the autophagy process in LF tissues for the first time. Quantitative RT-PCR, Western blotting, and immunohistochemistry results indicated that the mRNA and protein expression levels of FN1, TGFβ1, NGF, and HMOX1 significantly higher both in human and mouse with LFH, while the mRNA and protein expression levels of CAT and SIRT1 were significantly decreased.ConclusionBased on bioinformatics analysis and further experimental validation in clinical specimens and the BS mouse model, six potential ARGs including FN1, TGFβ1, NGF, HMOX1, CAT, and SIRT1 were found to participate in the fibrosis process of LFH through autophagy and play an essential role in its molecular mechanism. These potential genes may serve as specific therapeutic molecular targets in the treatment of LFH.

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ADAM10 promotes the proliferation of ligamentum flavum cells by activating the PI3K/AKT pathway

Cited by 7 publications

References 48 publications

Single-Cell RNA-Sequencing Reveals the Active Involvement of Macrophage Polarizations in Pulmonary Hypertension

Single-Cell RNA-Sequencing Reveals the Active Involvement of Macrophage Polarizations in Pulmonary Hypertension

Immune cell infiltration and the genes associated with ligamentum flavum hypertrophy: Identification and validation

Revealing the novel autophagy-related genes for ligamentum flavum hypertrophy in patients and mice model

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