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Series GSE216452 Query DataSets for GSE216452
Status Public on Apr 30, 2023
Title Modulation of lncRNA links endothelial glycocalyx to vascular dysfunction of tyrosine kinase inhibitors [dataset 1]
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary 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.
Overall design Comparative gene expression profiling analysis of RNA-seq data for three lines of hiPSC-EC treated with either DMSO or 1┬ÁM SUN for 72 hours
Contributor(s) Nukala S, Ong S
Citation(s) 37267414
Submission date Oct 24, 2022
Last update date Aug 11, 2023
Contact name Jordan Jousma
Organization name University of Illinois
Department Pharmacology and Regenerative Medicine
Street address 909 South Wolcott
City Chicago
State/province Illinois
ZIP/Postal code 60612
Country USA
Platforms (1)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
Samples (6)
GSM6674181 hiPSC-EC1, DMSO, 72Hr [Control 1]
GSM6674182 hiPSC-EC2, DMSO, 72Hr [Control 2]
GSM6674183 hiPSC-EC3, DMSO, 72Hr [Control 3]
This SubSeries is part of SuperSeries:
GSE216454 Modulation of lncRNA links endothelial glycocalyx to vascular dysfunction of tyrosine kinase inhibitors.
BioProject PRJNA893653

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SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE216452_SUN_raw_readcounts.txt.gz 313.7 Kb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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