Transcriptome profiling of Wnt5A activated human coronary artery endothelial cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE145987 | GEO | 2021/06/09
REPOSITORIES: GEO
Similar Datasets
Project description:IL-1b and Wnt5A are released from macrophages in systemic inflammation and sepsis. However, the early response targets for the paracrine action of synergistic interaction of IL-1b with Wnt5A in vascular endothelial cells still remain unclear. Here we show that IL-1b synergizes with Wnt5A to stimulate vascular endothelial inflammatory pathways involved in barrier dysfunction. Molecular targets involved in actin cytoskeleton remodeling, coagulation and stress signaling which are targets for known drugs are regulated by the synergistic action.
2021-06-09 | GSE146691 | GEO
Project description:Inflammatory Wnt5A signalling in human macrophages was found to be critically involved in severe systemic inflammatory response. However, the targets of Wnt5A in endothelial cells and downstream mechanisms by which Wnt5A might induce endothelial inflammation still remain unclear. We show that Wnt5A principally regulate genes involved endothelial cytoskeleton rearrangements and impairs the barrier function of cultured endothelial monolayer causing hyper permeability. We further prove that Wnt5A neither affects the expression of adhesion molecules nor induces cytokine storm in endothelial cells. These findings suggest that Wnt5A, secreted by activated macrophages during septic inflammation, paracrinically act on the endothelial wall, causing endothelial barrier breakdown and subsequent vascular leakage in sepsis.
2016-10-03 | GSE62281 | GEO
Project description:Upon activation, platelets release a host of soluble and vesicular signals, collectively termed the ‘platelet releasate’ (PR). The contents of this PR play a significant role in haemostasis, inflammation, and pathologic sequelae. Despite this, proteomic studies investigating the PR in coronary artery disease have not been performed. We undertook a comparative label-free quantitative (LFQ) proteomic profiling of the 1U/ml thrombin-induced PR from 13 acute coronary syndrome (ACS-STEMI) versus 14 stable angina pectoris patients using a tandem mass spectrometry approach. We identified differentially released platet proteins including tetranectin (CLEC3B), protein disulfide-isomerase-A3 (PDIA3), coagulation factor V (F5) and fibronectin (FN1). Strikingly, all 9 differential proteins were associated with the GO cellular component term ‘extracellular vesicle’ and reduced levels of EVs were detected in plasma of ACS-STEMI patients. Network analysis revealed 3 PR proteins either reduced (F5; FN1) or absent (CLEC3B) in ACS-STEMI patients, which are strongly connected to both the clotting cascade and major druggable targets on platelets. This moderated signature highlights the possible basis of platelet dysfunction in ACS-STEMI and may prove useful for non-invasive risk assessment of the progression of coronary artery disease.
2020-06-05 | PXD009356 | Pride
Project description:Transcriptome profiling of Wnt5A activated human coronary artery endothelial cells
| PRJNA608921 | ENA
Project description:IL-4 signalling is critically involved in Th2 driven allergic inflammatory responses. IL-4 generates a proinflammatory enviornment and may cause barrier dysfunction in vascular endothelial cells (VECs). However, the effectors responsible for IL-4 induced barrier dysfunction in adult human VECs still remain unclear. Here we show that IL-4 upregulates the expression of Wnt5A which can mediate cytoskeleton remodeling in VECs. We further show that IL-4 induced cytoskeleton remodeling involving stress fiber formation can be decreased by antagonizing Wnt5A. Further we demonstrate that silencing Wnt5A significantly improves the barrier function of IL-4 treated endothelial monolayer. Additionally, we rule out the involvement of IL-6 in IL-4 induced barrier dysfunction of VECs. These findings suggest a critical role for Wnt5A in mediating IL-4 induced endothelial barrier dysfunction and edem formation in Th2 driven inflammatory diseases.
2016-10-03 | GSE64860 | GEO
Project description:About half of all melanomas harbor a constitutively active mutant BRAFV600E/K kinase that can be selectively inhibited by targeted BRAF inhibitors (BRAFi). While patients treated with BRAFi initially exhibit measurable clinical improvement, the majority of patients eventually develop drug resistance and relapse. We observe significant elevation of WNT5A in a subset of tumors from patients exhibiting disease progression on BRAFi therapy. WNT5A transcript and protein are also elevated in BRAFi-resistant melanoma cell lines generated by long-term in vitro treatment with BRAFi. RNAi-mediated reduction in levels of endogenous WNT5A in melanoma decreases cell growth, increases apoptosis in response to BRAFi challenge, and decreases the activity of pro-survival AKT signaling. Overexpression of WNT5A conversely promotes melanoma growth and tumorigenesis and activates AKT signaling. Similar to WNT5A knockdown, knockdown of the WNT receptors FZD7 and RYK inhibits growth, sensitizes melanoma cells to BRAFi, and reduces AKT activation. Together, these findings suggest that chronic BRAF inhibition elevates WNT5A expression, which then acts through FZD7 and RYK to promote AKT signaling, leading to increased growth and therapeutic resistance. Increased WNT5A expression in BRAFi-resistant melanomas also correlates with an associated transcriptional signature, which identifies potential therapeutic targets to reduce clinical resistance to BRAFi. Expression of WNT5A-correlated genes was compared in melanoma cell lines generated to be resistant to PLX4032 and the their associated naïve parental line Basal expression of the WNT5A-correlated genes was also measured in experiments comparing each naïve line to a mixed reference pool containing equal amounts of 47 melanoma cell lines.
2014-03-06 | E-GEOD-55583 | biostudies-arrayexpress
Project description:Damage to our genome causes acute senescence in mammalian cells, which undergo growth arrest and release a secretome that elicits cell cycle arrest in bystander cells through the senescence-associated secretory phenotype (SASP). Thus, acute senescence is a powerful tumour suppressor. Salmonella enterica hijacks senescence through its typhoid toxin, which usurps unidentified factors in the stress secretome of senescent cells to mediate intracellular infections. Here, transcriptomics of toxin-induced senescent cells (txSCs) and proteomics of their secretome identified secreted ligands that activate the TGFβ pathway through SMAD transcription factors. The ligand Wnt5a established a self-amplifying positive feedback loop driving TGFβ signalling, which enforced autocrine senescence in txSCs and paracrine senescence in naive bystander cells by activation of DDRs. Wnt5a and GDF15 increased host cell susceptibility to infection. The study reveals how an innate defence against cancer is co-opted by a bacterial pathogen to cause widespread damage and mediate infections.
2023-09-07 | PXD037373 | Pride
Project description:Radiation therapy for abdominal tumors is challenging because the small intestine is exquisitely radiosensitive. Unfortunately, there are no FDA-approved therapies to prevent or mitigate GI radiotoxicity. The EGLN protein family are oxygen sensors that regulate cell survival and metabolism through the degradation of hypoxia-inducible factors (HIFs). Our group has previously shown that stabilization of HIF2 through genetic deletion or pharmacologic inhibition of the EGLNs mitigates and protects against GI radiotoxicity in mice by improving intestinal crypt stem cell survival. Here we aimed to elucidate the molecular mechanisms by which HIF2 confers GI radioprotection. We developed duodenal organoids from mice, transiently overexpressed non-degradable HIF2, and performed bulk RNA sequencing. Interestingly, HIF2 upregulated known radiation modulators and genes involved in GI homeostasis, including Wnt5a. Non-canonical Wnt5a signaling has been shown by other groups to improve intestinal crypt regeneration in response to injury. Here we show that HIF2 drives Wnt5a expression in multiple duodenal organoid models. Luciferase reporter assays performed in human cells showed that HIF2 directly activates the WNT5A promoter via a hypoxia response element. We then evaluated crypt regeneration using spheroid formation assays. Duodenal organoids that were pre-treated with recombinant Wnt5a had a higher cryptogenic capacity after irradiation, compared to vehicle-treated organoids. Conversely, we found that Wnt5a knockout decreased the cryptogenic potential of intestinal stem cells following irradiation. Treatment with recombinant Wnt5a prior to irradiation rescued the cryptogenic capacity of Wnt5a knockout organoids, indicating that Wnt5a is necessary and sufficient for duodenal radioprotection. Taken together, our results.txt suggest that HIF2 radioprotects the GI tract by inducing Wnt5a expression.
2021-12-15 | GSE186927 | GEO
Project description:Transcriptional profiling of E18.5 livers derived from Wnt5a-deficient (KO) mice compared to those from littermate wild-type (WT) mice. RNA samples were extracted from whole livers derived from E18.5 fetuses. Two-condition experiment: Wnt5a KO vs. WT whole livers. Total RNA samples were extracted from E18.5 whole livers. KO and WT samples were a mixture of RNA solutions derived from two Wnt5a KO livers and two WT livers, respectively.
2013-02-07 | E-GEOD-41803 | biostudies-arrayexpress
Project description:About half of all melanomas harbor a constitutively active mutant BRAFV600E/K kinase that can be selectively inhibited by targeted BRAF inhibitors (BRAFi). While patients treated with BRAFi initially exhibit measurable clinical improvement, the majority of patients eventually develop drug resistance and relapse. We observe significant elevation of WNT5A in a subset of tumors from patients exhibiting disease progression on BRAFi therapy. WNT5A transcript and protein are also elevated in BRAFi-resistant melanoma cell lines generated by long-term in vitro treatment with BRAFi. RNAi-mediated reduction in levels of endogenous WNT5A in melanoma decreases cell growth, increases apoptosis in response to BRAFi challenge, and decreases the activity of pro-survival AKT signaling. Overexpression of WNT5A conversely promotes melanoma growth and tumorigenesis and activates AKT signaling. Similar to WNT5A knockdown, knockdown of the WNT receptors FZD7 and RYK inhibits growth, sensitizes melanoma cells to BRAFi, and reduces AKT activation. Together, these findings suggest that chronic BRAF inhibition elevates WNT5A expression, which then acts through FZD7 and RYK to promote AKT signaling, leading to increased growth and therapeutic resistance. Increased WNT5A expression in BRAFi-resistant melanomas also correlates with an associated transcriptional signature, which identifies potential therapeutic targets to reduce clinical resistance to BRAFi.
2014-03-06 | GSE55583 | GEO