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 (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 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 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 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 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 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.

ADAMTS5 Promotes Permeability of the Blood-Brain Barrier during Treponema pallidum Subspecies pallidum Invading the Central Nervous System

“…The endothelial glycocalyx played a vital role in safeguarding the vascular endothelial barrier function. However, previous research indicated that ADAMTS5 could compromise the endothelial glycocalyx, leading to vascular endothelial dysfunction . To study the role of ADAMTS5 in the dysfunction of the barrier, we determined the expression of syndecan-1, which represented a major breakdown product of the glycocalyx, and hyaluronic acid in the CSF from HIV-negative patients with neurosyphilis.…”

“…Previous research had highlighted the capacity of ADAMTS5 to degrade the endothelial glycocalyx, an essential structure within the extracellular matrix of vascular endothelial cells. 23 The endothelial glycocalyx comprised a network of glycoproteins, proteoglycans, and hyaluronic acid lining the luminal surface of endothelial cells. 33,34 Notably, the glycocalyx of BBB played a critical role in various fundamental physiological functions, including the regulation of vascular permeability, inflammation, coagulation, and the synthesis of nitric oxide.…”

“…However, previous research indicated that ADAMTS5 could compromise the endothelial glycocalyx, leading to vascular endothelial dysfunction. 23 To study the role of ADAMTS5 in the dysfunction of the barrier, we determined the expression of syndecan-1, which represented a major breakdown product of the glycocalyx, 24 and hyaluronic acid in the CSF from HIV-negative patients with neurosyphilis. Results showed that both syndecan-1 and hyaluronic acid protein levels were notably up-regulated compared to the control (Figure 5A,B).…”

“…21,22 A deeper under- standing of ADAMTS5 revealed its involvement in the degradation of a critical structural component of the vascular endothelium's extracellular matrix, known as the endothelial glycocalyx. 23 The endothelial glycocalyx was an extracellular matrix layer that covered the surface of endothelial cells, primarily composed of heparan sulfate, chondroitin sulfate, and hyaluronic acid. 24 This layer formed a gel-like substance on the surface of endothelial cells.…”

“…ADAMTS5, a secreted metalloprotease, was known for its capacity to degrade aggrecan . Since its discovery in 1999, extensive research had focused primarily on conditions such as osteoarthritis and joint degeneration. − Notably, it had been observed that interleukin-1β (IL-1β) could up-regulate the expression of ADAMTS5 in human chondrocytes. , A deeper understanding of ADAMTS5 revealed its involvement in the degradation of a critical structural component of the vascular endothelium’s extracellular matrix, known as the endothelial glycocalyx . The endothelial glycocalyx was an extracellular matrix layer that covered the surface of endothelial cells, primarily composed of heparan sulfate, chondroitin sulfate, and hyaluronic acid .…”