{"doi":"10.1093/cvr/cvad087","title":"Modulation of lncRNA links endothelial glycocalyx to vascular dysfunction of tyrosine kinase inhibitor","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.","journal":"Cardiovascular Research","year":2023,"id":360743,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":295227,"name":"Jordan Jousma","orcid":"0000-0001-5434-2573","position":1,"is_corresponding":false},{"id":1057523,"name":"Gege Yan","orcid":"0000-0001-5923-4862","position":2,"is_corresponding":false},{"id":1112546,"name":"Zhenbo Han","orcid":"0000-0001-6892-5163","position":3,"is_corresponding":false},{"id":295224,"name":"Youjeong Kwon","orcid":"0000-0002-3915-8740","position":4,"is_corresponding":false},{"id":885196,"name":"Yoonje Cho","orcid":null,"position":5,"is_corresponding":false},{"id":1112547,"name":"Chuyu Liu","orcid":"0000-0002-4724-709X","position":6,"is_corresponding":false},{"id":399391,"name":"Keith T. Gagnon","orcid":"0000-0002-5868-675X","position":7,"is_corresponding":false},{"id":563744,"name":"Sandra Pinho","orcid":"0000-0002-5241-7364","position":8,"is_corresponding":false},{"id":235204,"name":"Jalees Rehman","orcid":"0000-0002-2787-9292","position":9,"is_corresponding":false},{"id":467617,"name":"Ning‐Yi Shao","orcid":"0000-0003-4231-828X","position":10,"is_corresponding":false},{"id":295228,"name":"Sang‐Bing Ong","orcid":"0000-0001-7421-2610","position":11,"is_corresponding":false},{"id":295229,"name":"Won Hee Lee","orcid":"0000-0001-8534-9639","position":12,"is_corresponding":false},{"id":259482,"name":"Sang‐Ging Ong","orcid":"0000-0003-0182-8769","position":13,"is_corresponding":false},{"id":295225,"name":"Sarath Babu Nukala","orcid":"0000-0002-0216-7168","position":0,"is_corresponding":true}],"reference_count":88,"raw_metadata":null,"created_at":"2026-07-19T01:14:06.433417Z","pmid":"37267414","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}