Modulation of lncRNA links endothelial glycocalyx to vascular dysfunction of tyrosine kinase inhibitor

Sarath Babu Nukala, Jordan Jousma, Gege Yan, Zhenbo Han, Youjeong Kwon, Yoonje Cho, Chuyu Liu, Keith Gagnon, Sandra Pinho, Jalees Rehman, Ning Yi Shao, Sang Bing Ong, Won Hee Lee, Sang Ging Ong

Research output: Contribution to journalArticlepeer-review

Abstract

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, 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 cell-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 down-regulate 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 confirmed 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 up-regulation 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 identified 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.

Original languageEnglish (US)
Pages (from-to)1997-2013
Number of pages17
JournalCardiovascular research
Volume119
Issue number10
DOIs
StatePublished - Aug 1 2023
Externally publishedYes

Keywords

  • Cardio-oncology
  • Glycocalyx
  • iPSCs
  • lncRNAs
  • Vascular toxicity

ASJC Scopus subject areas

  • General Medicine

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