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Superoxide dismutase-3 downmodulates laminin α5 expression in endothelial cells via Nuclear Factor kappa B signaling inhibition

ABSTRACT: The balance between laminins containing the α5 (LAMA5) or the α4 (LAMA4) subunits is determinant for the diapedesis of different leukocyte subtypes in inflammatory conditions. We have shown that the extracellular superoxide dismutase (SOD3) is a positive regulator of LAMA4, and this was associated with enhanced intratumor T cell infiltration in experimental and primary human cancers. Here we show that SOD3 overexpression in neoplastic or endothelial cells (ECs) downmodulates LAMA5 levels in implanted tumors. The inhibitory effect of SOD3 on LAMA5 expression occurs at the transcriptional level and is specific for SOD3, since LAMA5 levels are not changed by in SOD1-overexpressing cells. Global transcriptomic analyses revealed that SOD3 overexpression changes the transcription of 1,682 genes in ECs exposed to tumor secreted factors, being the canonical and non-canonical Nuclear Factor kappa B (NF-κB) pathways major SOD3 targets. Indeed, SOD3 reduced the transcription of well-known NF-κB target genes as well as the NF-κB-driven promoter activity in endothelial cells stimulated with tumor necrosis factor (TNF)-α, an inducer of NF-κB signaling

ORGANISM(S): Mus musculus

PROVIDER: GSE189247 | GEO | 2022/03/02

REPOSITORIES: GEO

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Extracellular Superoxide Dismutase Regulates the Expression of GTPase Guanine Nucleotide Exchange Factors (GEFs), GTPase-activating proteins (GAPs), and Rho Guanine nucleotide disassociation inhibitors (GDI)

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2020-06-01 | E-MTAB-7878 | biostudies-arrayexpress

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Multi-species RELA ChIP-seq of mammalian aortic endothelial cells before and after TNFα stimulation

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2019-05-09 | GSE95066 | GEO

LncRNA ICR regulates endothelium inflammation through feedback activation of NF-κB signaling

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2022-06-23 | GSE184512 | GEO

Human Toll-Like Receptors Pathway Array Data

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2011-11-04 | GSE33449 | GEO

Flow-induced reorganization of laminin-integrin networks within the endothelial basement membrane uncovered by proteomics

Project description:Objective The vessel wall is continuously exposed to hemodynamic forces generated by blood flow. Endothelial mechanosensors perceive and translate mechanical signals via cellular signaling pathways into biological processes that control endothelial development, phenotype and function. Here, we aim to unravel the molecular mechanisms underlying endothelial mechanosensing. Approach and results We applied a quantitative mass spectrometry approach combined with cell surface chemical footprinting to assess the hemodynamic effects on the endothelium on a system-wide level. These studies revealed that of the >5000 quantified proteins 104 were altered, which were highly enriched for extracellular matrix proteins and proteins involved in cell-matrix adhesion. Cell surface proteomics furthermore indicated that LAMA4 was proteolytically processed upon flow-exposure, which corresponded to the decreased LAMA4 mass observed on immunoblot. Immunofluorescence microscopy studies highlighted that the endothelial basement membrane was drastically remodeled upon flow exposure. We observed a network-like pattern of LAMA4 and LAMA5, which corresponded to the localization of laminin-adhesion molecules ITGA6 and ITGB4. Furthermore, the adaptation to flow-exposure did not affect the inflammatory response to tumor necrosis factor α, indicating that inflammation and flow trigger fundamentally distinct endothelial signaling pathways with limited reciprocity and synergy. Conclusions Taken together, this study uncovers the blood flow-induced remodeling of the basement membrane and stresses the importance of the subendothelial basement membrane in vascular homeostasis.

2020-04-29 | PXD014526 | Pride