Abstract
Oxidized-low density lipoprotein (ox-LDL) can induce injury of endothelial cells, causing atherosclerosis, which is an important initial event in several cardiovascular diseases. Long non-coding RNAs (lncRNAs) have emerged as regulators of diverse biological processes, but their specific biological functions and biochemical mechanisms in ox-LDL-induced endothelial cell injury have not been well investigated. Here, we describe the initial functional analysis of a poorly characterized human lncRNA ZEB1 antisense 1 (ZEB1-AS1). We found that ox-LDL treatment could induce a decreased cell viability and an increased cell apoptosis in endothelial cells, and knockdown of ZEB1-AS1 significantly reversed this effect. Mechanistically, ox-LDL treatment could sequester p53 from binding to ZEB1-AS1 promoter region, causing transcriptional activation and upregulation of ZEB1-AS1. Moreover, enhanced ZEB1-AS1 could upregulate Nucleotide-Binding Oligomerization Domain 2 (NOD2) expression through recruiting leucine-rich pentatricopeptide repeat motif-containing protein (LRPPRC) to stabilize NOD2 mRNA. Experimental data showed that knockdown of NOD2 or LRPPRC dramatically abrogated the functional role of ZEB1-AS1 in ox-LDL-induced endothelial cell injury. In summary, we demonstrated that lncRNA ZEB1-AS1 regulates the ox-LDL-induced endothelial cell injury via an LRPPRC-dependent mRNA stabilization mechanism. Therefore, ZEB1-AS1 may serve as a multi-potency target to overcome endothelial cell injury, atherosclerosis and other cardiovascular diseases.
Highlights
The dysfunction of endothelial cells (ECs), which is closely related with endothelial damage, play key roles in the initiation and progression of atherosclerosis (AS) (Blann, 1999)
To investigate the functional role of ZEB1-AS1 in ox-LDLinduced human umbilical vein endothelial cells (HUVECs) injury, we treated the HUVECs with 100 μg/ml Oxidized-low density lipoprotein (ox-LDL)
We silenced ZEB1-AS1 in HUVECs by using specific silencing oligonucleotides (Figure 1B), and si-ZEB1-AS1#2 was used for further experiments
Summary
The dysfunction of endothelial cells (ECs), which is closely related with endothelial damage, play key roles in the initiation and progression of atherosclerosis (AS) (Blann, 1999). LncRNAs are involved in complex biological processes through diverse mechanisms. These comprise, among others, gene regulation by titration of transcription factors, alternative splicing, sponging of microRNAs, and recruitment of chromatin modifying enzymes (Kornienko et al, 2013; Fatica and Bozzoni, 2014; Nakagawa and Kageyama, 2014; Ni et al, 2017). Accumulating evidence indicates that lncRNAs play diverse roles in the AS and ECs dysfunction, such as MALAT1 (Gast et al, 2018), ANRIL (Holdt and Teupser, 2018), and H19 (Pan, 2017). Functional potentials of other lncRNAs are waiting to be revealed
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