AUTHOR=Kai Huihua , Wu Qiyong , Yin Ruohan , Tang Xiaoqiang , Shi Haifeng , Wang Tao , Zhang Ming , Pan Changjie 

TITLE=LncRNA NORAD Promotes Vascular Endothelial Cell Injury and Atherosclerosis Through Suppressing VEGF Gene Transcription via Enhancing H3K9 Deacetylation by Recruiting HDAC6

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=9

YEAR=2021

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.701628

DOI=10.3389/fcell.2021.701628

ISSN=2296-634X

ABSTRACT=<p>Coronary artery disease (CAD) is a major atherosclerotic cardiovascular disease and the leading cause of mortality globally. Long non-coding RNAs (lncRNAs) play crucial roles in CAD development. To date, the effect of lncRNA non-coding RNA activated by DNA damage (NORAD) on atherosclerosis in CAD remains unclear. The primary aim of this study was to investigate the effect of lncRNA NORAD on vascular endothelial cell injury and atherosclerosis. Here, ox-LDL-treated human umbilical vein endothelial cells (HUVECs) and high-fat-diet (HFD)-fed ApoE<sup>–/–</sup> mice were utilized as <italic>in vitro</italic> and <italic>in vivo</italic> models. The present study found that lncRNA NORAD expression was increased in ox-LDL-treated HUVECs and thoracic aorta of atherosclerotic mice, and knockdown of lncRNA NORAD alleviated vascular endothelial cell injury and atherosclerosis development <italic>in vitro</italic> and <italic>in vivo</italic>. Knockdown of lncRNA NORAD aggravated ox-LDL-reduced or atherosclerosis-decreased vascular endothelial growth factor (VEGF) expression in HUVECs and thoracic aorta of mice to ameliorate vascular endothelial cell injury and atherosclerosis development. Moreover, nucleus lncRNA NORAD suppressed <italic>VEGF</italic> gene transcription through enhancing H3K9 deacetylation <italic>via</italic> recruiting HDAC6 to the <italic>VEGF</italic> gene promoter in ox-LDL-treated HUVECs. In addition, VEGF reduced FUS (FUS RNA binding protein) expression by a negative feedback regulation in HUVECs. In summary, lncRNA NORAD enhanced vascular endothelial cell injury and atherosclerosis through suppressing <italic>VEGF</italic> gene transcription <italic>via</italic> enhancing H3K9 deacetylation by recruiting HDAC6. The findings could facilitate discovering novel diagnostic markers and therapeutic targets for CAD.</p>