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

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

doi:10.3389/fcell.2021.701628

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

Front Cell Dev Biol. 2021 Jul 9:9:701628. doi: 10.3389/fcell.2021.701628. eCollection 2021.

Authors

Huihua Kai¹, Qiyong Wu², Ruohan Yin¹, Xiaoqiang Tang¹, Haifeng Shi¹, Tao Wang¹, Ming Zhang¹, Changjie Pan¹

Affiliations

¹ Department of Radiology, Changzhou Second People's Hospital Affiliated to Nanjing Medical University, Changzhou, China.
² Department of Thoracic and Cardiac Surgery, Changzhou Second People's Hospital Affiliated to Nanjing Medical University, Changzhou, China.

Abstract

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^-/- mice were utilized as in vitro and in vivo 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 in vitro and in vivo. 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 VEGF gene transcription through enhancing H3K9 deacetylation via recruiting HDAC6 to the VEGF 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 VEGF gene transcription via enhancing H3K9 deacetylation by recruiting HDAC6. The findings could facilitate discovering novel diagnostic markers and therapeutic targets for CAD.

Keywords: VEGF; atherosclerosis; coronary artery disease; histone deacetylation; lncRNA NORAD; vascular endothelial cell injury.