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Knockdown of Long Noncoding RNA (lncRNA) AK094457 Relieved Angiotensin II Induced Vascular Endothelial Cell Injury.

ABSTRACT: BACKGROUND Hypertension could induce many serious diseases, including damage to vascular endothelial cells. As a non-coding RNA, long noncoding RNA (lncRNA) has received much attention in scientific research and has a regulating efficacy on many critical life activities in human body. The level of lncRNA AK094457 is thought to be elevated in hypertensive rats. However, there is no research indicating the relationship between the level of lncRNA AK094457 and vascular endothelial injury. MATERIAL AND METHODS In our study, we used lentiviral to knockdown lncRNA AK094457, and the human umbilical vein endothelial cells (HUVECs) were stimulated by the Ang II to imitate the vascular endothelial cell damage caused by hypertension. The Cell Counting Kit-8 assays were used to detect the cells viability. Western blotting was performed to detect the endothelial nitric oxide synthase (eNOS), p-eNOS and endothelin-1 (ET-1). After that the production of the NO was monitored. At last, the reactive oxygen species (ROS) levels and apoptosis rates were detected in this study. RESULTS According to the results, we found that knockdown lncRNA AK094457 could alleviate the decrease of vascular endothelial cell viability induced by angiotensin II (Ang II). The knockdown of lncRNA AK094457 also relieved the downregulation of eNOS and p-eNOS, and the decreasing of NO release. At the same time, the knockdown of lncRNA inhibited the levels of Ang II-induced proinflammatory cytokines (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1, and IL-6) and cell adhesion molecules (vascular cell adhesion molecule 1 [VCAM-1], intercellular adhesion molecule 1 [ICAM-1], and monocyte chemoattractant protein-1 [MCP-1]). The levels of ROS and apoptosis rates also decreased after the knockdown of lncRNA AK094457. CONCLUSIONS All these results indicated that lncRNA AK094457 could promote Ang II-induced vascular endothelial cell injury. On the contrary, knockdown of lncRNA AK094457 could alleviate this damage.

SUBMITTER: Xu J

PROVIDER: S-EPMC7020760 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Knockdown of Long Noncoding RNA (lncRNA) AK094457 Relieved Angiotensin II Induced Vascular Endothelial Cell Injury.

Xu JiaYi J Sun Yingjie Y Lu Jie J

Medical science monitor : international medical journal of experimental and clinical research 20200206

BACKGROUND Hypertension could induce many serious diseases, including damage to vascular endothelial cells. As a non-coding RNA, long noncoding RNA (lncRNA) has received much attention in scientific research and has a regulating efficacy on many critical life activities in human body. The level of lncRNA AK094457 is thought to be elevated in hypertensive rats. However, there is no research indicating the relationship between the level of lncRNA AK094457 and vascular endothelial injury. MATERIAL ...[more]

PMID: 32027625

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Project description:RATIONALE:AngII (angiotensin II)-mediated vascular smooth muscle cell (VSMC) dysfunction plays a major role in hypertension. Long noncoding RNAs have elicited much interest, but their molecular roles in AngII actions and hypertension are unclear. OBJECTIVE:To investigate the regulation and functions of a novel long noncoding RNA growth factor- and proinflammatory cytokine-induced vascular cell-expressed RNA ( Giver), in AngII-mediated VSMC dysfunction. METHODS AND RESULTS:RNA-sequencing and real-time quantitative polymerase chain reactions revealed that treatment of rat VSMC with AngII increased the expression of Giver and Nr4a3, an adjacent gene encoding a nuclear receptor. Similar changes were observed in rat and mouse aortas treated ex vivo with AngII. RNA-FISH (fluorescence in situ hybridization) and subcellular fractionation showed predominantly nuclear localization of Giver. AngII increased Giver expression via recruitment of Nr4a3 to Giver promoter. Microarray profiling and real-time quantitative polymerase chain reaction validation in VSMC showed that Giver knockdown attenuated the expression of genes involved in oxidative stress ( Nox1) and inflammation ( Il6, Ccl2, Tnf) but increased Nr4a3. Conversely, endogenous Giver overexpression showed opposite effects supporting its role in oxidative stress and inflammation. Chromatin immunoprecipitation assays showed Giver overexpression also increased Pol II (RNA polymerase II) enrichment and decreased repressive histone modification histone H3 trimethylation on lysine 27 at Nox1 and inflammatory gene promoters. Accordingly, Giver knockdown inhibited AngII-induced oxidative stress and proliferation in rat VSMC. RNA-pulldown combined with mass spectrometry showed Giver interacts with nuclear and chromatin remodeling proteins and corepressors, including NONO (non-pou domain-containing octamer-binding protein). Moreover, NONO knockdown elicited similar effects as Giver knockdown on the expression of key Giver-regulated genes. Notably, GIVER and NR4A3 were increased in AngII-treated human VSMC and in arteries from hypertensive patients but attenuated in hypertensive patients treated with ACE (angiotensin-converting enzyme) inhibitors or angiotensin receptor blockers. Furthermore, human GIVER also exhibits partial functional conservation with rat Giver. CONCLUSIONS:Giver and its regulator Nr4a3 are important players in AngII-mediated VSMC dysfunction and could be novel targets for antihypertensive therapy.

Dataset Information

Knockdown of Long Noncoding RNA (lncRNA) AK094457 Relieved Angiotensin II Induced Vascular Endothelial Cell Injury.

Publications

Knockdown of Long Noncoding RNA (lncRNA) AK094457 Relieved Angiotensin II Induced Vascular Endothelial Cell Injury.

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