Dataset Information

BLTR1 in Monocytes Emerges as a Therapeutic Target For Vascular Inflammation With a Subsequent Intimal Hyperplasia in a Murine Wire-Injured Femoral Artery.

ABSTRACT: Given the importance of high-mobility group box 1 (HMGB1) and 5-lipoxygenase (5-LO) signaling in vascular inflammation, we investigated the role of leukotriene signaling in monocytes on monocyte-to-macrophage differentiation (MMD) induced by HMGB1, and on vascular inflammation and subsequent intimal hyperplasia in a mouse model of wire-injured femoral artery. In cultured primary bone marrow-derived cells (BMDCs) stimulated with HMGB1, the number of cells with macrophage-like morphology was markedly increased in association with an increased expression of CD11b/Mac-1, which were attenuated in cells pre-treated with Zileuton, a 5-LO inhibitor as well as in 5-LO-deficient BMDCs. Of various leukotriene receptor inhibitors examined, which included leukotriene B4 receptors (BLTRs) and cysteinyl leukotriene receptors (cysLTRs), the BLTR1 inhibitor (U75302) exclusively suppressed MMD induction by HMGB1. The importance of BLTR1 in HMGB1-induced MMD was also observed in BMDCs isolated from BLTR1-deficient mice and BMDCs transfected with BLTR1 siRNA. Although leukotriene B4 (LTB4) had minimal direct effects on MMD in control and 5-LO-deficient BMDCs, MMD attenuation by HMGB1 in 5-LO-deficient BMDCs was significantly reversed by exogenous LTB4, but not in BLTR1-deficient BMDCs, suggesting that LTB4/BLTR1-mediated priming of monocytes is a prerequisite of HMGB1-induced MMD. In vivo, both macrophage infiltration and intimal hyperplasia in our wire-injured femoral artery were markedly attenuated in BLTR1-deficient mice as compared with wild-type controls, but these effects were reversed in BLTR1-deficient mice transplanted with monocytes from control mice. These results suggest that BLTR1 in monocytes is a pivotal player in MMD with subsequent macrophage infiltration into neointima, leading to vascular remodeling after vascular injury.

SUBMITTER: Baek SE

PROVIDER: S-EPMC6121004 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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BLTR1 in Monocytes Emerges as a Therapeutic Target For Vascular Inflammation With a Subsequent Intimal Hyperplasia in a Murine Wire-Injured Femoral Artery.

Baek Seung E SE Park So Y SY Bae Sun S SS Kim Koanhoi K Lee Won S WS Kim Chi D CD

Frontiers in immunology 20180828

Given the importance of high-mobility group box 1 (HMGB1) and 5-lipoxygenase (5-LO) signaling in vascular inflammation, we investigated the role of leukotriene signaling in monocytes on monocyte-to-macrophage differentiation (MMD) induced by HMGB1, and on vascular inflammation and subsequent intimal hyperplasia in a mouse model of wire-injured femoral artery. In cultured primary bone marrow-derived cells (BMDCs) stimulated with HMGB1, the number of cells with macrophage-like morphology was marke ...[more]

PMID: 30210495

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Project description:Intimal hyperplasia (IH) is a prominent pathological event that occurs during in-stent restenosis and atherosclerosis. Ferroptosis, characterized by iron-dependent and lipid peroxidation, has become the recent focus of studies on the occurrence and progress of cardiovascular diseases. However, there are few studies on ferroptosis and IH. Therefore, we aimed to identify and validate ferroptosis-related markers in IH to explore new possibilities for IH diagnosis and treatment. The IH microarray dataset (GSE182291) was downloaded from the Gene Expression Omnibus (GEO) database and ferroptosis-related genes (FRGs) were obtained from the FerrDb databases. The differentially expressed genes (DEGs) were analyzed using the GEO2R. Overlapping was performed to identify the ferroptosis-related DEGs among the DEGs and FRGs. Then, clustering, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein-protein interaction (PPI) analyses were performed. Subsequently, the hub genes were identified using Cytoscape and hub gene-transcription factors and hub gene-microRNA networks were constructed. Finally, real-time qPCR (RT-qPCR) and immunohistochemistry (IHC) were used to verify the mRNA and protein levels of the hub FRGs in IH. Thirty-four FRGs showing significantly different expression were identified from a total of 1,197 DEGs 2 days after ligation; 31 FRGs were selected from a total of 1,556 DEGs 14 days after ligation. The GO and KEGG analyses revealed that these 34 ferroptosis-related DEGs identified 2 days after ligation were mainly enriched in the basolateral plasma membrane, ferroptosis, lipid and atherosclerosis, and IL-17 signaling pathways. The 31 ferroptosis-related DEGs in endometrial hyperplasia identified 14 days after ligation were mainly enriched in response to oxidative stress, ferroptosis, tumor necrosis factor signaling pathway, and lipid and atherosclerosis. Five hub FRGs (Il1b, Ptgs2, Cybb, Cd44, and Tfrc) were identified using PPI networks; four hub FRGs (Il1b, Ptgs2, Cybb, and Cd44) were validated to be upregulated 2 and 14 days after ligation using RT-qPCR and show significantly different expression 14 days after ligation via IHC. Our findings verify the expression of hub DEGs related to ferroptosis in IH and elucidate the potential relationship between ferroptosis and IH, providing more evidence about the vital role of ferroptosis in IH.

Dataset Information

BLTR1 in Monocytes Emerges as a Therapeutic Target For Vascular Inflammation With a Subsequent Intimal Hyperplasia in a Murine Wire-Injured Femoral Artery.

Publications

BLTR1 in Monocytes Emerges as a Therapeutic Target For Vascular Inflammation With a Subsequent Intimal Hyperplasia in a Murine Wire-Injured Femoral Artery.

Similar Datasets

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