Cancer is one of the leading causes of morbidity and mortality worldwide. Significant improvements in the modern era of anticancer therapeutic strategies have increased the survival rate of cancer patients. Unfortunately, cancer survivors have an increased risk of cardiovascular diseases, which is believed to result from anticancer therapies. The emergence of cardiovascular diseases among cancer survivors has served as the basis for establishing a novel field termed cardio-oncology. Cardio-oncology primarily focuses on investigating the underlying molecular mechanisms by which anticancer treatments lead to cardiovascular dysfunction and the development of novel cardioprotective strategies to counteract cardiotoxic effects of cancer therapies. Advances in genome biology have revealed that most of the genome is transcribed into non-coding RNAs (ncRNAs), which are recognized as being instrumental in cancer, cardiovascular health, and disease. Emerging studies have demonstrated that alterations of these ncRNAs have pathophysiological roles in multiple diseases in humans. As it relates to cardio-oncology, though, there is limited knowledge of the role of ncRNAs. In the present review, we summarize the up-to-date knowledge regarding the roles of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in cancer therapy-induced cardiotoxicities. Moreover, we also discuss prospective therapeutic strategies and the translational relevance of these ncRNAs.

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.

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.