Modulation of lncRNA links endothelial glycocalyx to vascular dysfunction of tyrosine kinase inhibitors.
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ABSTRACT:
PROVIDER: PRJNA893634 | ENA |
REPOSITORIES: ENA
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Project description:Aims: Novel cancer therapies leading to increased survivorship of cancer patients have been negated by a concomitant rise in cancer therapies-related cardiovascular toxicities. Sunitinib, a first line multi receptor tyrosine kinase inhibitor (TKI), has been reported to cause vascular dysfunction although the initiating mechanisms contributing to this side effect remain unknown. Long non-coding RNAs (lncRNAs) are emerging regulators of biological processes in endothelial cells (ECs); however, their roles in cancer therapies-related vascular toxicities remain underexplored. Methods and Results: We performed lncRNA expression profiling to identify potential lncRNAs that are dysregulated in human induced pluripotent stem cells-derived ECs (iPSC-ECs) treated with sunitinib. We show that the lncRNA hyaluronan synthase 2 antisense 1 (HAS2-AS1) is significantly diminished in sunitinib-treated iPSC-ECs. Sunitinib was found to downregulate HAS2-AS1 by an epigenetic mechanism involving hypermethylation. Depletion of HAS2-AS1 recapitulated sunitinib-induced detrimental effects on iPSC-ECs, whereas CRISPR-mediated activation of HAS2-AS1 reversed sunitinib-induced dysfunction. We confirm that HAS2-AS1 stabilizes the expression of its sense gene HAS2 via an RNA/mRNA heteroduplex formation. Knockdown of HAS2-AS1 led to reduced synthesis of hyaluronic acid (HA) and upregulation of ADAMTS5, an enzyme involved in extracellular matrix degradation, resulting in disruption of the endothelial glycocalyx which is critical for ECs. In vivo, sunitinib-treated mice showed reduced coronary flow reserve, accompanied by a reduction in has2os and degradation of the endothelial glycocalyx. Finally, we identify that treatment with high molecular-weight HA can prevent the deleterious effects of sunitinib both in vitro and in vivo by preserving the endothelial glycocalyx. Conclusions: Our findings highlight the importance of lncRNA-mediated regulation of the endothelial glycocalyx as an important determinant of sunitinib-induced vascular toxicity and reveal potential novel therapeutic avenues to attenuate sunitinib-induced vascular dysfunction.
2023-04-30 | GSE216453 | GEO
Project description:Aims: Novel cancer therapies leading to increased survivorship of cancer patients have been negated by a concomitant rise in cancer therapies-related cardiovascular toxicities. Sunitinib, a first line multi receptor tyrosine kinase inhibitor (TKI), has been reported to cause vascular dysfunction although the initiating mechanisms contributing to this side effect remain unknown. Long non-coding RNAs (lncRNAs) are emerging regulators of biological processes in endothelial cells (ECs); however, their roles in cancer therapies-related vascular toxicities remain underexplored. Methods and Results: We performed lncRNA expression profiling to identify potential lncRNAs that are dysregulated in human induced pluripotent stem cells-derived ECs (iPSC-ECs) treated with sunitinib. We show that the lncRNA hyaluronan synthase 2 antisense 1 (HAS2-AS1) is significantly diminished in sunitinib-treated iPSC-ECs. Sunitinib was found to downregulate HAS2-AS1 by an epigenetic mechanism involving hypermethylation. Depletion of HAS2-AS1 recapitulated sunitinib-induced detrimental effects on iPSC-ECs, whereas CRISPR-mediated activation of HAS2-AS1 reversed sunitinib-induced dysfunction. We confirm that HAS2-AS1 stabilizes the expression of its sense gene HAS2 via an RNA/mRNA heteroduplex formation. Knockdown of HAS2-AS1 led to reduced synthesis of hyaluronic acid (HA) and upregulation of ADAMTS5, an enzyme involved in extracellular matrix degradation, resulting in disruption of the endothelial glycocalyx which is critical for ECs. In vivo, sunitinib-treated mice showed reduced coronary flow reserve, accompanied by a reduction in has2os and degradation of the endothelial glycocalyx. Finally, we identify that treatment with high molecular-weight HA can prevent the deleterious effects of sunitinib both in vitro and in vivo by preserving the endothelial glycocalyx. Conclusions: Our findings highlight the importance of lncRNA-mediated regulation of the endothelial glycocalyx as an important determinant of sunitinib-induced vascular toxicity and reveal potential novel therapeutic avenues to attenuate sunitinib-induced vascular dysfunction.
2023-04-30 | GSE216452 | GEO
Project description:Modulation of lncRNA links endothelial glycocalyx to vascular dysfunction of tyrosine kinase inhibitors [dataset 2]
| PRJNA893654 | ENA
Project description:Modulation of lncRNA links endothelial glycocalyx to vascular dysfunction of tyrosine kinase inhibitors [dataset 1]
| PRJNA893653 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-04-30 | GSE216454 | GEO
Project description:Acute Respiratory Distress Syndrome (ARDS) is a common cause of respiratory failure yet has few pharmacologic therapies, reflecting the mechanistic heterogeneity of lung injury. We hypothesized that damage to the alveolar epithelial glycocalyx, a layer of glycosaminoglycans interposed between the epithelium and surfactant, contributes to lung injury in ARDS patients. Using mass spectrometry of airspace fluid noninvasively collected from mechanically-ventilated patients, we found that airspace glycosaminoglycan shedding (an index of glycocalyx degradation) occurred predominantly in patients with direct lung injury and was associated with duration of mechanical ventilation. Male patients had increased shedding which correlated with airspace concentrations of matrix metalloproteinases. Selective epithelial glycocalyx degradation in mice was sufficient to induce surfactant dysfunction, a key characteristic of ARDS, leading to microatelectasis and decreased lung compliance. Rapid colorimetric quantification of airspace glycosaminoglycans was feasible and could provide point-of-care prognostic information to clinicians and/or be used for predictive enrichment in clinical trials.
2021-12-07 | GSE186705 | GEO
Project description:Markers of endothelial glycocalyx dysfunction in Clarkson disease
| PRJNA842668 | ENA
Project description:Background Clarkson disease is a rare idiopathic condition marked by transient, relapsing-remitting episodes of systemic microvascular hyper-permeability, which liberates plasma fluid and macromolecules into the peripheral tissues. This pathology manifests clinically as the abrupt onset of hypotensive shock, he-moconcentration, and hypoalbuminemia. Methods We analysed endothelial glycocalyx (eGCX)-related markers in plasma from patients with SCLS dur-ing acute disease flares and convalescence by ELISA and comprehensive proteomic profiling. eGCX-related components and gene expression in cultured endothelial cells were evaluated by RNA-sequencing, real-time PCR, and fluorescence. Results Serum levels of eGCX-related core components including hyaluronic acid (HA) and/or the core pro-teoglycan soluble syndecan-1 (sCD138) were elevated at baseline and during acute SCLS flares. Se-rial measurements in several patients demonstrated that sCD138 levels peaked during the recovery (post-leak) phase of the illness. Proteomic analysis of matched acute and convalescent SCLS plasma revealed increased abundance of eGCX-related proteins, including glypicans, thrombospondin-1 (TSP-1), and eGCX-degrading enzymes in acute plasma compared to remission plasma. Abundance of endothelial cell damage markers did not differ in acute and baseline plasma. Expression of several eGCX-related genes and surface carbohydrate content in endothelial cells from patients with SCLS did not differ significantly from that observed in healthy control cells. Conclusions eGCX dysfunction, but not endothelial injury, may contribute to clinical symptoms of acute SCLS. Serum levels of of eGCX components including sCD138 may be measured during acute episodes of SCLS to monitor clinical status and therapeutic responses.
2022-05-29 | GSE204882 | GEO
Project description:Objective: Considerable evidence links dietary salt intake with the development of hypertension, left ventricular hypertrophy, and increased risk of stroke and coronary heart disease. Despite extensive epidemiological and basic science interrogation of the relationship between high salt (HS) intake and blood pressure, it remains unclear how HS impacts endothelial cell (EC) and vascular structure in vivo. This study aims to uncover the HS-induced vascular pathologies using a differential systemic decellularization in vivo (DISDIVO) approach.Approach and Results: We performed systematic molecular characterization of the endothelial glycocalyx (eGC) and EC proteomes in mice with HS (8%) diet-induced hypertension versus healthy control animals. Isolation of eGC and ECs compartments was achieved using the DISDIVO approach. Altered protein expression in hypertensive compared to normal mice was characterized by liquid chromatography tandem-mass spectrometry (LC-MS/MS). Proteomic results from eGC fractions revealed a significant downregulation of eGC and associated proteins in HS diet-induced hypertensive mice. Among 1696 proteins identified in this group, 723 were markedly downregulated while 168 were upregulated, bioinformatic analysis indicates critical damage and derangement of eGC layer. In the ECs fraction HS-induced hypertension significantly altered protein mediators of contractility, metabolism, mechanotransduction, renal functions, and coagulation cascades. In particular, we observed dysregulation of integrin subunits alpha2, alpha2b, and alpha5, which relay external signals to the actin cytoskeleton.Conclusion: These findings provide novel molecular insight on HS-induced structure changes in eGC and ECs that may increase cardiovascular risk and potentially guide the development of new diagnostics and therapeutic interventions.
2023-10-24 | PXD031228 | Pride
Project description:The intestine is under constant exposure to chemicals, antigens and microorganisms from the external environment. Apical aspects of absorptive epithelial cells form a brush border membrane (BBM), shaped by packed microvilli coated with a dense glycocalyx. We present evidence showing that the glycocalyx forms an epithelial barrier that prevents exogenous molecules and live bacteria from gaining access to BBM. We used a multi-omics approach to investigate function and regulation of membrane mucins exposed on the BBM during postnatal development of the mouse small intestine. Muc17 was identified as a major membrane mucin in the glycocalyx that was specifically upregulated by IL-22 as part of an epithelial defense repertoire during weaning. High levels of IL-22 at time of weaning reprogrammed neonatal postmitotic progenitor enterocytes to differentiate into Muc17-expressing enterocytes, as found in adult intestine during homeostasis. Our findings propose a role for Muc17 in epithelial barrier function in small intestine.
2021-02-16 | GSE164552 | GEO