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Sustained and intermittent hypoxia differentially modulate primary monocyte immunothrombotic responses to IL-1b stimulation

ABSTRACT: We replicated the intricate conditions of the venous valve pocket using a state-of-the-art hypoxia chamber with software-controlled oxygen cycling. We comprehensively studied the effects of sustained and intermitted hypoxia alone or in combination with IL-1b to mimic VTE-associated inflammatory stimuli on primary monocytes. Our transcriptome analysis revealed that sustained hypoxia limited the pro-inflammatory response induced by IL-1b, and triggered a metabolic shift in the monocyte transcriptome. On the other hand, intermittent hypoxia alone had a modest effect, but in combination with IL-1b it significant altered the expression of 2207 genes. Notably, intermittent hypoxia enhanced the IL-1b -stimulatory effects on several chemokine and interleukin genes (e.g., IL-19, IL-24, IL-32, MIF), as well as genes involved in coagulation (thrombomodulin) and fibrinolysis (VEGFA, MMP9, MMP14 and PAI-1. The RNA seq data are paired with validations on protein level in the published paper. Our findings provide valuable insights into how the different hypoxic profiles shape the immunothrombotic response of monocytes and shed new light on the early events in the pathogenesis of venous thrombosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234701 | GEO | 2023/06/15

REPOSITORIES: GEO

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Sustained and intermittent hypoxia combined with TNF additively promote pro-thrombotic gene and protein changes in primary endothelial cells.

Project description:Venous thromboembolism (VTE) is a common and deadly disease with unclear pathophysiological initiation. Hypoxia and inflammation are believed to contribute to promoting thrombosis, but how and if these potential triggers interact is unclear. We have stimulated primary endothelial cells with sustained and intermittent hypoxia, in the presence or absence of TNF. Effects to the cells were analyzed with RNA sequencing and flow cytometry after 24H and 48H stimulations. RNA sequencing confirmed strong pro-inflammatory effects of TNF, and indicated that hypoxia alone had modest effects, but when combined with TNF there were clear additive effects on the number of differentially expressed genes, as well as modest increases of pro-inflammatory GO terms assessed by GSEA. On protein level, flow cytometry confirmed additive effects of combingin hypoxia and TNF for several adhesion molecules including E-selectin and ICAM-1, as well as on associated molecules including tissue factor. Unsupervised clustering of the flow cytometric data also revealed the expansion of a subset of endothelial cells with strongly pro-thrombotic phenotype. Taken together, our data suggests that hypoxia combines with inflammatory cues in the in vivo situation to promote pro-thrombotic responses by endothelial cells in the venous valve pocket.

2023-09-17 | GSE243023 | GEO

Transcription profiling of mouse macrophage response to hypoxia, part 2

Project description:We hypothesize that the culture media collected from macrophages exposed to intermittent hypoxia will induce a greater pro-inflammatory gene profile in naïve cultured macrophages than will culture media collected from macrophages exposed to sustained hypoxia. We will evaluate gene expression using microarray analysis of RNA collected from RAW 264.7 macrophages cultured for 24 hours in DMEM media obtained from 1) cells cultured with intermittent hypoxia (2 minute cycles: 90 seconds at 40 Torr and 30 seconds at 8 Torr), 2) media exposed to intermittent hypoxia, 3) cells cultured with sustained hypoxia (8 Torr), 4) media exposed to sustained hypoxia and 4) standard tissue culture conditions (fresh DMEM media; reference).

2005-01-01 | E-TIGR-91 | biostudies-arrayexpress

Differential expression of genes involved in the transtion to Doxorubicin drug resistance in MCF7 breast cancer cells

Project description:Summary: Cancer imparts an increased risk for venous thromboembolism (VTE). Direct mechanisms linking VTE with malignancy remain unknown. Our characterization of Doxorubicin (DOX)-resistant MCF7 breast cancer cells revealed links with antithrombotic pathways, as an anticoagulant transcriptional profile was observed. Specifically, the intracellular anticoagulant Tissue Factor Pathway Inhibitor 1 (TFPI1) protein was elevated and functional in all resistant models tested; TFPI1 accumulation coincided with reduced thrombin. TFPI1 overexpression in unselected cells elevated pro-malignant gene markers and increased DOX resistance. Furthermore, TFPI1 and Breast Cancer Resistant Protein (BCRP) levels increased early and remained sustained during selection. Finally, consistent with antithrombin-mediated hypoxic metastasis, Hypoxia-Inducible Factor 1 alpha (HIF1alpha) was elevated in drug resistant and TFPI1 overexpressing cells. Thus, increased TFPI1 may create an intratumoral hypoxic environment, potentially leading to drug resistance. MCF7 cells were selected for DOX resistance by first treating the cells with 1 microM DOX for 48 hours. The cells were then exposed to 100 nM DOX for 2 weeks. After this period, the surviving cells were resistant to further DOX treatment.

2013-06-01 | E-MTAB-1643 | biostudies-arrayexpress

Transcription profiling of mouse macrophage response to hypoxia, part 1

Project description:We hypothesize that cultured macrophages directly exposed intermittent hypoxia will have a greater change in expression in genes related to inflammatory response than macrophages exposed to sustained hypoxia. We will evaluate gene expression using microarray analysis of RNA collected from RAW 264.7 macrophages cultured under the following environmental conditions: 1) 4 hours of intermittent hypoxia (2 minute cycles: 90 seconds at 40 Torr and 30 seconds at 8 Torr), 2) 4 hours of sustained hypoxia (8 Torr), and 3 ) standard tissue culture conditions (141 Torr; reference).

2005-01-01 | E-TIGR-90 | biostudies-arrayexpress

Whole Blood Gene Expression Profiles Distinguish Patients with Single versus Recurrent Venous Thromboembolism

Project description:Venous thromboembolism (VTE) is a major cause of morbidity and mortality. Pulmonary embolism is a life threatening manifestation of VTE that occurs in at least half the patients on presentation. In addition, VTE recurs in up to 30% of patients after a standard course of anticoagulation, and there is not a reliable way of predicting recurrence. We investigated whether gene expression profiles of whole blood could distinguish patients with VTE from healthy controls, single VTE from those with recurrence, and DVT alone from those with PE. 70 adults with VTE on warfarin and 63 healthy controls were studied. Patients with antiphospholipid syndrome or cancer were excluded. Blood was collected in PAXgene tubes, RNA isolated, and gene expression profiles obtained using Affymetrix arrays. We developed a 50 gene model that distinguished healthy controls from subjects with VTE with excellent receiver operating characteristics (AUC 0.94; P < 0.0001). We also discovered a separate 50 gene model that distinguished subjects with a single VTE from those with recurrent VTE with good receiver operating characteristics (AUC 0.75; P=0.008). In contrast, we were unable to distinguish subjects with DVT from those with PE using gene expression profiles. Gene expression profiles of whole blood can distinguish subjects with VTE from healthy controls and subjects with a single VTE from those with recurrence. Additional studies should be performed to validate these results and develop diagnostic tests. Gene expression profiling is likely translatable to other thrombotic disorders(e.g., patients with cancer and VTE).

2011-11-10 | GSE19151 | GEO

Whole Blood Gene Expression Profiles Distinguish Patients with Single versus Recurrent Venous Thromboembolism

2011-11-10 | E-GEOD-19151 | biostudies-arrayexpress

Temporal effects of intermittent- and sustained hypoxia on gene expression patterns in rat lungs

Project description:Time-course gene expression profiles were obtained from lung tissues of the rats treated with room air, intermittent- (IH) or sustained hypoxia (SH) for 1, 3, 7, 14 and 30 days using CodeLink microarrays. Using a systems biology approach, we observed that two different mechanisms are involved in the lung responses to IH and SH: IH leads to increased G-protein coupled signaling-, ion transport-, neuronal- and steroid hormone receptor activities; whereas SH causes increased blood vessel morphogenesis and immune responses. Our results provide insight into molecular mechanisms underlying IH and SH. Keywords: gene expression array-based, count rats were treated with intermittent- (IH) or sustained hypoxia (SH) for 1, 3, 7, 14 and 30 days; rats treated with room air were used as controls; gene expression profiles were obtained from these rats

2008-12-17 | E-GEOD-8705 | biostudies-arrayexpress

Phase III study of efficacy of fondaparinux on the prevention of post-operative venous thromboembolism in patients undergoing with laparoscopic colorectal cancer surgery.

Project description:Interventions: Once daily fondaparinux (2.5mg or 1.5mg) for 4 to 8 days after 24 hours of surgery Intermittent pneumatic compression according to the institutional guidelines Primary outcome(s): Incidence of venous thromboembolism (VTE) Study Design: Parallel Randomized

| 2623843 | ecrin-mdr-crc