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.
Highlights
Coronary artery disease (CAD) is a major cardiovascular disease, which is considered as the leading cause of mortality globally (Khera and Kathiresan, 2017; Malakar et al, 2019)
Results showed that Long non-coding RNAs (lncRNAs) non-coding RNA activated by DNA damage (NORAD) expression was increased in ox-LDL-treated human umbilical vein endothelial cells (HUVECs) compared to that in control HUVECs treated without ox-LDL (Figure 1B) (p < 0.01)
The above data had indicated that knockdown of lncRNA NORAD ameliorated vascular endothelial injury in AS mice, and we further identified the effect of lncRNA NORAD on atherosclerosis; AS mice were injected with shRNA interference vector of lncRNA NORAD (shNORAD) or shCtrl
Summary
Coronary artery disease (CAD) is a major cardiovascular disease, which is considered as the leading cause of mortality globally (Khera and Kathiresan, 2017; Malakar et al, 2019). According to a Chinese Ministry of Health report, more than 1 million people die from CAD in China annually (Wang et al, 2017). In United States, about 6 million deaths occur due to CAD each year (Lloyd-Jones et al, 2009). The incidence of CAD rises rapidly (Lloyd-Jones et al, 2009). CAD has been a major global health concern. It is urgent to discover novel diagnostic markers and therapeutic targets for CAD
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