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LncRNA ZEB1-AS1 Mediates Oxidative Low-Density Lipoprotein-Mediated Endothelial Cells Injury by Post-transcriptional Stabilization of NOD2.

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.

SUBMITTER: Xu X

PROVIDER: S-EPMC6477043 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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lncRNA ZEB1-AS1 Mediates Oxidative Low-Density Lipoprotein-Mediated Endothelial Cells Injury by Post-transcriptional Stabilization of NOD2.

Xu Xiaohui X Ma Congmin C Duan Zhihui Z Du Yanjiao Y Liu Chao C

Frontiers in pharmacology 20190416

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 ...[more]

PMID: 31040785

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Project description:Oxidized low?density lipoprotein (ox?LDL)?induced vascular endothelial damage, oxidative stress and inflammation play a vital role in the pathophysiology of atherosclerosis. Geniposide is the primary active ingredient from Gardenia jasminoides Ellis associated with anti?oxidative properties and cardioprotective action. However, the therapeutic mechanism of geniposide in atherosclerosis remains unclear. Hence, the present study aimed to elucidate the underlying mechanisms of geniposide in oxidative stress and inflammatory response during ox?LDL injury in human umbilical vein endothelial cells (HUVECs), focusing particularly on the microRNA (miR)?21/PTEN pathway. The results demonstrated that geniposide pretreatment significantly increased cell viability, decreased lactate dehydrogenase release, increased miR?21 level and decreased PTEN expression under ox?LDL condition. Subsequently, transfection with miR?21 mimic enhanced the protection of geniposide on ox?LDL?induced cytotoxicity and apoptosis (mediated by the upregulation of apoptotic rate and caspase?3 activity), whereas miR?21 inhibitor reversed these effects of geniposide. In addition, geniposide resulted in an anti?oxidant effect as evidenced by the decrease in reactive oxygen species generation, malondialdehyde content and NADPH oxidase 2 expression, and the increase in superoxide dismutase, glutathione peroxidase and catalase activities in ox?LDL?treated HUVECs, which were exacerbated by miR?21 mimic and reversed by miR?21 inhibitor. Furthermore, geniposide mitigated the ox?LDL?induced inflammatory response, demonstrated by a downregulation of pro?inflammatory cytokine (IL?1?, IL?6, and TNF??) levels and an upregulation of anti?inflammatory cytokine (IL?10) level. However, miR?21 mimic enhanced, whereas miR?21 inhibitor attenuated, these effects of geniposide. In conclusion, the present results indicated that geniposide protects HUVECs from ox?LDL injury by inhibiting oxidative stress and inflammation, and that these effects are partly due to the enhancement of the miR?21/PTEN pathway.

Dataset Information

LncRNA ZEB1-AS1 Mediates Oxidative Low-Density Lipoprotein-Mediated Endothelial Cells Injury by Post-transcriptional Stabilization of NOD2.

Publications

lncRNA ZEB1-AS1 Mediates Oxidative Low-Density Lipoprotein-Mediated Endothelial Cells Injury by Post-transcriptional Stabilization of NOD2.

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