Abstract
Circular RNAs (circRNAs) are classified as non‐coding RNA that form covalently closed continuous loops and act as gene regulators in physiological and disease conditions. We hypothesize that proatherogenic lipid lysophosphatidylcholine (LPC) induce a set of circRNAs in human aortic endothelial cell (HAEC) activation. We performed circRNA analysis by searching our RNA‐Seq data from LPC‐activated HAECs and found: 1) LPC induce significant modulation of 77 newly characterized cirRNAs, among which 47 circRNAs (61%) are upregulated; 2) 34 (72%) out of 47 upregulated circRNAs are upregulated when the corresponding mRNAs are downregulated, suggesting that the majority of circRNAs are upregulated presumably via LPC‐induced “abnormal splicing” when the canonical splicing for generation of corresponding mRNAs is suppressed; 3) Upregulation of 47 circRNAs is associated with LPC‐upregulated cholesterol synthesis‐SREBP2 pathway and LPC‐downregulated TGF‐β pathway; 4) increased upstream chromatin long‐range interaction sites to circRNA related genes favor circRNA generation over canonical splicing for mRNAs, suggesting that shifting chromatin long‐range interaction sites from downstream to upstream promotes induction of a list of circular RNAs in lysoPC‐activated human aortic endothelial cells; 5) six significantly changed circRNAs may have sponge functions for miRNAs; and 6) 74% significantly changed circRNAs contain open reading frames, suggesting that short proteins may interfere the protein interaction‐based signaling. Our finding have demonstrated for the first time that a new set of LPC‐induced circRNAs may contribute to proatherogenic LPC‐induced HAEC activation. These novel insights may lead to identification of new therapeutic targets for treating metabolic cardiovascular diseases, inflammations and cancers.Support or Funding InformationThis work was supported by NIH grants to Drs. XF Yang and H Wang.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Highlights
Cardiovascular diseases remain some of the most prevalent health challenges today
Among 109 miRNAs that we examined in all four hyperlipidemia-related diseases (HRDs), namely atherosclerosis, non-alcoholic fatty liver disease (NAFLD), obesity and type II diabetes (T2DM), miR-155 and miR221 are significantly modulated in these HRDs
The importance of circular RNA (circRNA) in regulating endothelial cell (EC) function has been reported, the comprehensive analyses of circRNAs in EC activation, EC function, and cardiovascular diseases remain at their infancy; the characterization of circRNAs in atherosclerosis-relevant Human aortic endothelial cell (HAEC) has not been reported (Maass et al, 2017; Huang et al, 2018; Shang et al, 2018)
Summary
Cardiovascular diseases remain some of the most prevalent health challenges today. Predominant among these, atherosclerosis and resultant ischemic heart disease, stroke, and peripheral artery disease are estimated to cause 8.9 million deaths per year, making it the single most significant cause of death worldwide (Wang H. et al, 2016). We and others have reported that hyperlipidemia, together with other CVD risk factors, such as hyperglycemia, chronic kidney disease, obesity, and hyperhomocysteinemia (HHcy), promotes atherosclerosis development via several mechanisms These mechanisms include endothelial cell (EC) activation and injury (Shao et al, 2014; Yin et al, 2015; Li et al, 2016a, 2018a); monocyte recruitment and differentiation (Combadière et al, 2008; Fang et al, 2014); decreased function of regulatory T cells (Tregs) (Ait-Oufella et al, 2006; Yan et al, 2008; Li et al, 2017); transdifferentiation of Tregs into antigen-presenting cell (APC) like Tregs (Xu et al, 2018); impaired vascular repairability of bone marrow-derived progenitor cells (Du et al, 2012; Barbier et al, 2015; Li et al, 2016b); increased migration and proliferation of vascular smooth muscle cells (Monroy et al, 2015; Ferrer et al, 2016), and high fatinduced adipocyte hypertrophy and metabolic healthy obesity (Virtue et al, 2017). The regulatory mechanisms underpinning these physiological changes remain poorly understood; and whether and how noncoding RNAs (ncRNAs) mechanisms control HAEC activation remains poorly characterized
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