Hsa-miRNA-23a-3p promotes atherogenesis in a novel mouse model of atherosclerosis

Guo, Jiayan; Mei, Hanbing; Sheng, Zhonghua; Meng, Qing‐Yuan; Véniant, Murielle M.; Yin, Hang

doi:10.1194/jlr.ra120001121

Cited by 15 publications

(7 citation statements)

References 74 publications

(65 reference statements)

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“…These newly observed interactions were not previously linked to cHL pathogenesis. However, Guo et al observed recently, using in vivo mouse and in vitro human cell models, that has-miR-23a-3p regulates inflammation and apoptosis by interacting with TNFAIP3 in atherosclerosis [37]. In line, this was the strongest interaction observed in our reporter assay experiments, suggesting that overexpression of this miRNA is an alternative and most probably a more subtle mechanism to the recurrent loss of function genomic alterations targeting TNFAIP3 in cHL [17].…”

Section: Discussionsupporting

confidence: 69%

Deregulated miRNAs Contribute to Silencing of B-Cell Specific Transcription Factors and Activation of NF-κB in Classical Hodgkin Lymphoma

Paczkowska

Janiszewska

Ustaszewski

et al. 2021

Cancers

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A hallmark of classical Hodgkin lymphoma (cHL) is the attenuation of B-cell transcription factors leading to global transcriptional reprogramming. The role of miRNAs (microRNAs) involved in this process is poorly studied. Therefore, we performed global miRNA expression profiling using RNA-seq on commonly used cHL cell lines, non-Hodgkin lymphoma cell lines and sorted normal CD77+ germinal centre B-cells as controls and characterized the cHL miRNome (microRNome). Among the 298 miRNAs expressed in cHL, 56 were significantly overexpressed and 23 downregulated (p < 0.05) compared to the controls. Moreover, we identified five miRNAs (hsa-miR-9-5p, hsa-miR-24-3p, hsa-miR-196a-5p, hsa-miR-21-5p, hsa-miR-155-5p) as especially important in the pathogenesis of this lymphoma. Target genes of the overexpressed miRNAs in cHL were significantly enriched (p < 0.05) in gene ontologies related to transcription factor activity. Therefore, we further focused on selected interactions with the SPI1 and ELF1 transcription factors attenuated in cHL and the NF-ĸB inhibitor TNFAIP3. We confirmed the interactions between hsa-miR-27a-5p:SPI1, hsa-miR-330-3p:ELF-1, hsa-miR-450b-5p:ELF-1 and hsa-miR-23a-3p:TNFAIP3, which suggest that overexpression of these miRNAs contributes to silencing of the respective genes. Moreover, by analyzing microdissected HRS cells, we demonstrated that these miRNAs are also overexpressed in primary tumor cells. Therefore, these miRNAs play a role in silencing the B-cell phenotype in cHL.

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Section: Discussionsupporting

confidence: 69%

Deregulated miRNAs Contribute to Silencing of B-Cell Specific Transcription Factors and Activation of NF-κB in Classical Hodgkin Lymphoma

Paczkowska

Janiszewska

Ustaszewski

et al. 2021

Cancers

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“…The miR-23 cluster is highly expressed in EC and has been implicated in processes supporting angiogenesis ( 58 – 60 ). MiR-23 has also been implicated in atherogenesis, potentially by supporting a proinflammatory secretome in HCAEC ( 61 ) and has been linked to cardiomyopathy in mice ( 62 ). miR-126 has been implicated in the promotion of angiogenesis, however, numerous additional functions have also been observed.…”

Section: Discussionmentioning

confidence: 99%

Endothelial cell-derived extracellular vesicles impair the angiogenic response of coronary artery endothelial cells

Carter

Mathiesen

Miller

et al. 2022

Front. Cardiovasc. Med.

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Cardiovascular disease (CVD) is the most prominent cause of death of adults in the United States with coronary artery disease being the most common type of CVD. Following a myocardial event, the coronary endothelium plays an important role in the recovery of the ischemic myocardium. Specifically, endothelial cells (EC) must be able to elicit a robust angiogenic response necessary for tissue revascularization and repair. However, local or distant cues may prevent effective revascularization. Extracellular vesicles (EV) are produced by all cells and endothelium is a rich source of EVs that have access to the main circulation thereby potentially impacting local and distant tissue function. Systemic inflammation associated with conditions such as obesity as well as the acute inflammatory response elicited by a cardiac event can significantly increase the EV release by endothelium and alter their miRNA, protein or lipid cargo. Our laboratory has previously shown that EVs released by adipose tissue endothelial cells exposed to chronic inflammation have angiostatic effects on naïve adipose tissue EC in vitro. Whether the observed effect is specific to EVs from adipose tissue endothelium or is a more general feature of the endothelial EVs exposed to pro-inflammatory cues is currently unclear. The objective of this study was to investigate the angiostatic effects of EVs produced by EC from the coronary artery and adipose microvasculature exposed to pro-inflammatory cytokines (PIC) on naïve coronary artery EC. We have found that EVs from both EC sources have angiostatic effects on the coronary endothelium. EVs produced by cells in a pro-inflammatory environment reduced proliferation and barrier function of EC without impacting cellular senescence. Some of these functional effects could be attributed to the miRNA cargo of EVs. Several miRNAs such as miR-451, let-7, or miR-23a impact on multiple pathways responsible for proliferation, cellular permeability and angiogenesis. Collectively, our data suggests that EVs may compete with pro-angiogenic cues in the ischemic myocardium therefore slowing down the repair response. Acute treatments with inhibitors that prevent endogenous EV release immediately after an ischemic event may contribute to better efficacy of therapeutic approaches using functionalized exogenous EVs or other pro-angiogenic approaches.

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“…Gene‐set enrichment analysis (GSEA, https://www.gsea-msigdb.org/gsea/index.jsp) of the signaling pathways was performed as described by LC‐Bio (https://www.lc-bio.cn/). Publicly available transcriptome data GSE94044 (Mohanta et al , 2022b; Data ref: Mohanta et al , 2022a) and GSE137581 (Guo et al , 2020b; Data ref: Guo et al , 2020a) were acquired from the Gene Expression Omnibus database (https://www.ncbi.nlm.nih.gov/geo/). DEGs were selected with fold change > 2 or fold change < 0.5 and P ‐value < 0.05, using GEO2R.…”

Section: Methodsmentioning

confidence: 99%

Macrophage DCLK1 promotes atherosclerosis via binding to IKKβ and inducing inflammatory responses

et al. 2023

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Atherosclerosis is a chronic inflammatory disease with high morbidity and mortality rates worldwide. Doublecortin-like kinase 1 (DCLK1), a microtubule-associated protein kinase, is involved in neurogenesis and human cancers. However, the role of DCLK1 in atherosclerosis remains undefined. In this study, we identified upregulated DCLK1 in macrophages in atherosclerotic lesions of ApoE −/− mice fed an HFD and determined that macrophagespecific DCLK1 deletion attenuates atherosclerosis by reducing inflammation in mice. Mechanistically, RNA sequencing analysis indicated that DCLK1 mediates oxLDL-induced inflammation via NF-κB signaling pathway in primary macrophages. Coimmunoprecipitation followed by LC-MS/MS analysis identified IKKβ as a binding protein of DCLK1. We confirmed that DCLK1 directly interacts with IKKβ and phosphorylates IKKβ at S177/181, thereby facilitating subsequent NF-κB activation and inflammatory gene expression in macrophages. Finally, a pharmacological inhibitor of DCLK1 prevents atherosclerotic progression and inflammation both in vitro and in vivo. Our findings demonstrated that macrophage DCLK1 promotes inflammatory atherosclerosis by binding to IKKβ and activating IKKβ/NF-κB. This study reports DCLK1 as a new IKKβ regulator in inflammation and a potential therapeutic target for inflammatory atherosclerosis.

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Hsa-miRNA-23a-3p promotes atherogenesis in a novel mouse model of atherosclerosis

Cited by 15 publications

References 74 publications

Deregulated miRNAs Contribute to Silencing of B-Cell Specific Transcription Factors and Activation of NF-κB in Classical Hodgkin Lymphoma

Deregulated miRNAs Contribute to Silencing of B-Cell Specific Transcription Factors and Activation of NF-κB in Classical Hodgkin Lymphoma

Endothelial cell-derived extracellular vesicles impair the angiogenic response of coronary artery endothelial cells

Macrophage DCLK1 promotes atherosclerosis via binding to IKKβ and inducing inflammatory responses

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