Abstract
Introduction: Novel cancer therapies leading to increased survivorship of cancer patients have been negated by a concomitant rise in cancer therapies-related cardiotoxicities. Sunitinib, a multi receptor tyrosine kinase inhibitor, has been reported to cause vascular toxicity. Long non-coding RNAs (lncRNAs) are emerging regulators of biological processes in endothelial cells (ECs); however, their role in cardio-oncology remains poorly understood. Hypothesis: We hypothesize that lncRNAs may be involved in sunitinib-induced endothelial dysfunction and may represent a target class amenable for therapeutic action. Methods and Results: We performed lncRNA expression profiling to identify potential lncRNA candidates that are dysregulated in human induced pluripotent stem cells-derived ECs (hiPSC-ECs) treated with sunitinib. We discovered sunitinib epigenetically repressed the expression of lncRNA hyaluronan synthase 2 antisense 1 (HAS2-AS1). Downstream mechanistic studies revealed that HAS2-AS1 stabilizes the expression of its sense gene HAS2 via RNA/mRNA heteroduplex formation. Knockdown of HAS2-AS1 led to reduced production of hyaluronic acid (HA) and aggrecan, two major constituents of the endothelial glycocalyx (EG), resulting in decreased viability, impaired angiogenesis, and increased vascular permeability. Supplementation of sunitinib-treated hiPSC-ECs with HA or overexpression of HAS2 restored the integrity of the glycocalyx and prevented sunitinib-induced endothelial dysfunction. These results were further validated in an in vivo mouse model of sunitinib-induced dysfunction as shown by reduced coronary flow reserve (CFR), degraded EG within the aorta, and increased vascular permeability. Conclusions: Our study established that deficiency of HAS2-AS1, coupled with reduced production of HA that is essential for proper glycocalyx formation, may be responsible for sunitinib-induced endothelial damage. Therapeutic strategies targeting the extracellular matrix components of the glycocalyx may represent a broad strategy to prevent sunitinib-induced endothelial dysfunction.
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