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

Autor:	Nukala SB; Department of Pharmacology & Regenerative Medicine, The University of Illinois College of Medicine, 909 S Wolcott Ave, Chicago, IL 60607, USA., Jousma J; Department of Pharmacology & Regenerative Medicine, The University of Illinois College of Medicine, 909 S Wolcott Ave, Chicago, IL 60607, USA., Yan G; Department of Pharmacology & Regenerative Medicine, The University of Illinois College of Medicine, 909 S Wolcott Ave, Chicago, IL 60607, USA., Han Z; Department of Pharmacology & Regenerative Medicine, The University of Illinois College of Medicine, 909 S Wolcott Ave, Chicago, IL 60607, USA., Kwon Y; Department of Pharmacology & Regenerative Medicine, The University of Illinois College of Medicine, 909 S Wolcott Ave, Chicago, IL 60607, USA., Cho Y; Department of Pharmacology & Regenerative Medicine, The University of Illinois College of Medicine, 909 S Wolcott Ave, Chicago, IL 60607, USA., Liu C; Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR 999078, China., Gagnon K; Division of Biochemistry and Molecular Biology, School of Medicine, Southern Illinois University, 1245 Lincoln Drive Carbondale, IL 62901-4413, USA.; Department of Chemistry and Biochemistry, Southern Illinois University, 1245 Lincoln Drive, Carbondale IL 62901, USA., Pinho S; Department of Pharmacology & Regenerative Medicine, The University of Illinois College of Medicine, 909 S Wolcott Ave, Chicago, IL 60607, USA., Rehman J; Department of Pharmacology & Regenerative Medicine, The University of Illinois College of Medicine, 909 S Wolcott Ave, Chicago, IL 60607, USA.; Division of Cardiology, Department of Medicine, The University of Illinois College of Medicine, 840 S Wood Street, Chicago, IL 60612, USA., Shao NY; Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR 999078, China., Ong SB; Department of Medicine and Therapeutics, Faculty of Medicine, Chinese University of Hong Kong (CUHK), 9/F, Lui Che Woo Clinical Sciences Building, Prince of Wales Hospital, Shatin, N.T., Hong Kong, China.; Centre for Cardiovascular Genomics and Medicine (CCGM), Lui Che Woo Institute of Innovative Medicine, 10/F, Lui Che Woo Clinical Sciences Building, Prince of Wales Hospital, Shatin, N.T., Hong Kong, China.; Hong Kong Hub of Paediatric Excellence (HK HOPE), Hong Kong Children's Hospital (HKCH), 8/F, Tower A,1 Shing Cheong Road, Kowloon Bay, Hong Kong, China.; Kunming Institute of Zoology - The Chinese University of Hong Kong (KIZ-CUHK) Joint Laboratory of Bioresources and Molecular Research of Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China., Lee WH; Department of Basic Medical Sciences, University of Arizona College of Medicine, 425 North 5th Street, Phoenix, AZ 85004, USA., Ong SG; Department of Pharmacology & Regenerative Medicine, The University of Illinois College of Medicine, 909 S Wolcott Ave, Chicago, IL 60607, USA.; Department of Medicine and Therapeutics, Faculty of Medicine, Chinese University of Hong Kong (CUHK), 9/F, Lui Che Woo Clinical Sciences Building, Prince of Wales Hospital, Shatin, N.T., Hong Kong, China.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2023 Aug 19; Vol. 119 (10), pp. 1997-2013.
DOI:	10.1093/cvr/cvad087
Abstrakt:	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. Competing Interests: Conflict of interest: None declared. (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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