Contributions of Costimulatory Molecule CD137 in Endothelial Cells

Yuan, Wei; Xu, Chong; Li, Bo; Xia, Hao; Pan, Yingjie; Zhong, Wei; Xu, Liang; Chen, Rui; Wang, Bin

doi:10.1161/jaha.120.020721

Cited by 11 publications

(7 citation statements)

References 53 publications

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“…Upregulation of CD137 in ECs leads to endothelial dysfunction, which subsequently increases the expression of adhesion molecules on ECs and pro-in ammatory cytokine production by them; both of these processes augment the recruitment and migration of leukocytes to exacerbate atherosclerotic process 7,8 . Based on the above ndings, it is conceivable that a high-dose systemic exposure of PTX upregulates mediators that are known to trigger cascades of secondary events increasing the atherothrombotic process in the vasculature.…”

Section: Discussionmentioning

confidence: 99%

“…CKS2 interacts with cyclin-dependent kinases to regulate the cell cycle and is associated with atherosclerosis 6 . CD137 mediates adhesion molecules on ECs and mediates EC dysfunction and pro-in ammatory cytokine response 7,8 . MCP-1 is a well-established pro-in ammatory cytokine associated with atherothrombotic diseases 41,42 .…”

Section: Paclitaxel Compromises Fundamental Endothelial Cell Function...mentioning

confidence: 99%

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Alleviating iatrogenic effects of paclitaxel via anti-inflammatory treatment

Zhang

Lotfollahzadeh

Elzinad

et al. 2023

Preprint

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Background Paclitaxel is touted as an essential medicine due to its extensive use as a chemotherapeutic for various cancers and an antiproliferative agent for restenosis. Due to recent concerns related to long-term mortality, paclitaxel (PTX)-based endovascular therapy is now surrounded by controversies. Objective Examine the inflammatory mediators driven by the systemic administration of PTX and explore the means to suppress these effects. Methods RNAseq analysis, cell and mouse models. Results RNAseq analysis of primary human endothelial cells (ECs) treated with PTX demonstrated transcriptional perturbations of a set of pro-inflammatory mediators, including monocyte chemoattractant protein-1 (MCP-1) and CD137, which were validated in EC lysates. These perturbations were abrogated with dexamethasone, a prototypic anti-inflammatory compound. The media of ECs pre-treated with PTX showed a significant increase in MCP-1 levels, which were reverted to baseline levels with DEX treatment. A group of mice harvested at different time points after PTX injection were analyzed for immediate and delayed effects of PTX. A 3-fold increase in MCP-1 was noted in blood and aortic ECs after 12 hours of PTX treatment. Similar changes in CD137 and downstream mediators such as tissue factor, VCAM-1 and E-selectin were noted in aortic ECs. Conclusions Our study shows that systemic PTX exposure upregulates atherothrombotic markers, and co-delivery of DEX can subdue the untoward toxic effects. Long-term studies are needed to probe the mechanisms driving systemic complications of PTX-based therapies and evaluate the clinical potential of DEX to mitigate risk.

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Section: Discussionmentioning

confidence: 99%

Section: Paclitaxel Compromises Fundamental Endothelial Cell Function...mentioning

confidence: 99%

Alleviating iatrogenic effects of paclitaxel via anti-inflammatory treatment

Zhang

Lotfollahzadeh

Elzinad

et al. 2023

Preprint

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“…CD137 (TNFRSF9) is expressed in a variety of immunocytes and nonimmune cells, including ECs and smooth muscle cells. CD137 is involved in several known biological functions in ECs, including inflammation, angiogenesis, and apoptosis [ 51 ]. Previous studies have shown that the expression of CD137 is upregulated in atheroma-associated vascular cells in both mouse and human atherosclerotic plaque lesions in vivo [ 52 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

Whole-Transcriptome Sequencing Analyses of Nuclear Antixoxidant-1 in Endothelial Cells: Role in Inflammation and Atherosclerosis

Varadarajan

Shi

Kaplan

et al. 2022

Cells

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Inflammation, oxidative stress, and copper (Cu) play an important role in cardiovascular disease, including atherosclerosis. We previously reported that cytosolic Cu chaperone antioxidant-1 (Atox1) translocates to the nucleus in response to inflammatory cytokines or exogenous Cu and that Atox1 is localized at the nucleus in the endothelium of inflamed atherosclerotic aorta. However, the roles of nuclear Atox1 and their function are poorly understood. Here we showed that Atox1 deficiency in ApoE−/− mice with a Western diet exhibited a significant reduction of atherosclerotic lesion formation. In vitro, adenovirus-mediated overexpression of nuclear-targeted Atox1 (Ad-Atox1-NLS) in cultured human endothelial cells (ECs) increased monocyte adhesion and reactive oxygen species (ROS) production compared to control cells (Ad-null). To address the underlying mechanisms, we performed genome-wide mapping of Atox1-regulated targets in ECs, using an unbiased systemic approach integrating sequencing data. Combination of ChIP-Seq and RNA-Seq analyses in ECs transfected with Ad-Atox1-NLS or Ad-null identified 1387 differentially expressed genes (DEG). Motif enrichment assay and KEGG pathway enrichment analysis revealed that 248 differentially expressed genes, including inflammatory and angiogenic genes, were regulated by Atox1-NLS, which was then confirmed by real-time qPCR. Among these genes, functional analysis of inflammatory responses identified CD137, CSF1, and IL5RA as new nuclear Atox1-targeted inflammatory genes, while CD137 is also a key regulator of Atox1-NLS-induced ROS production. These findings uncover new nuclear Atox1 downstream targets involved in inflammation and ROS production and provide insights into the nuclear Atox1 as a potential therapeutic target for the treatment of inflammatory diseases such as atherosclerosis.

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“… 118 There are also reports of 4–1BB expression on nonimmune cells like adipocytes 119 and atherosclerosis- or cancer-induced 4–1BB expression on blood vessel endothelial cells. 120 , 121 4–1BB agonism has both pathogenic and protective role in type 1 diabetes mouse models 122 , 123 and obesity-induced inflammations. 119 , 124 All this may play a role in the 4–1BB-mediated MoA as well as irAEs, and has to be carefully considered.…”

Section: Clinical Safety and Functionalitymentioning

confidence: 99%

The emerging landscape of novel 4-1BB (CD137) agonistic drugs for cancer immunotherapy

Claus

Ferrara-Koller

Klein

2023

mAbs

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The clinical development of 4–1BB agonists for cancer immunotherapy has raised substantial interest during the past decade. The first generation of 4–1BB agonistic antibodies entering the clinic, urelumab (BMS-663513) and utomilumab (PF-05082566), failed due to (liver) toxicity or lack of efficacy, respectively. The two antibodies display differences in the affinity and the 4–1BB receptor epitope recognition, as well as the isotype, which determines the Fc-gamma-receptor (FcγR) crosslinking activity. Based on this experience a very diverse landscape of second-generation 4–1BB agonists addressing the liabilities of first-generation agonists has recently been developed, with many entering clinical Phase 1 and 2 studies. This review provides an overview focusing on differences and their scientific rationale, as well as challenges foreseen during the clinical development of these molecules.

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Contributions of Costimulatory Molecule CD137 in Endothelial Cells

Cited by 11 publications

References 53 publications

Alleviating iatrogenic effects of paclitaxel via anti-inflammatory treatment

Alleviating iatrogenic effects of paclitaxel via anti-inflammatory treatment

Whole-Transcriptome Sequencing Analyses of Nuclear Antixoxidant-1 in Endothelial Cells: Role in Inflammation and Atherosclerosis

The emerging landscape of novel 4-1BB (CD137) agonistic drugs for cancer immunotherapy

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