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
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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.
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Project description:Transcriptome profiling of Wnt5A activated human coronary artery endothelial cells
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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.
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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.
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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.
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