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Sulforaphane protects human umbilical vein endothelial cells from oxidative stress via the miR-34a/SIRT1 axis by upregulating nuclear factor erythroid-2-related factor 2.

ABSTRACT: Oxidative stress-induced vascular endothelial cell dysfunction serves an essential role in the initiation and development of atherosclerosis. Sulforaphane (SFN), a naturally occurring antioxidant, has previously demonstrated to exert protective effects on the endothelium against oxidative stress. However, further studies are required to determine its underlying molecular mechanism prior to clinical application. Accumulating evidence suggests that alterations in the microRNA (miRNA/miR)-34a/sirtuin-1 (SIRT1) axis occur with oxidative stress. Therefore, the present study aimed to investigate if SFN exerts a protective role against oxidative stress in vascular endothelial cells through regulation of the miR-34a/SIRT1 axis. Human umbilical vein endothelial cells (HUVECs) were treated with H₂O₂ in the presence or absence of SFN pretreatment. Cell viability and apoptosis were analyzed using CellTiter-Blue and flow cytometry, respectively. Reverse transcription-quantitative PCR and western blot analyses were performed to determine changes in the expression levels of miR-34a and SIRT1. The expression levels of miR-34a and SIRT1 were artificially regulated following transfection with miR-34a mimic and inhibitor or SIRT1expression plasmid and small interfering RNA, respectively. Subsequently, the effect of the expression changes of miR-34 and SIRT1 on oxidative stress-induced cell injury was investigated. Dual-luciferase reporter assay was used to confirm the targeted binding of miR-34a to SIRT1. SFN was found to ameliorate cellular damage caused by H₂O₂ and inhibited intracellular reactive oxygen species production. In addition, miR-34a upregulation was accompanied with reduced SIRT1 expression in HUVECs, following H₂O₂ treatment. miR-34a was revealed to directly target SIRT1 by binding to its 3'-untranslated region. Down-regulation of miR-34a and up-regulation of SIRT1 increased the survival of HUVECs under oxidative stress. Taken together, the results of the present study suggest that SFN may protect HUVECs from oxidative stress by inducing changes in the miR-34a/SIRT1 axis via upregulation of nuclear factor erythroid-2-related factor 2 expression.

SUBMITTER: Li T

PROVIDER: S-EPMC7812584 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Sulforaphane protects human umbilical vein endothelial cells from oxidative stress via the miR-34a/SIRT1 axis by upregulating nuclear factor erythroid-2-related factor 2.

Li Tao T Pang Qi Q Liu Yongbin Y Bai Ming M Peng Yu Y Zhang Zheng Z

Experimental and therapeutic medicine 20210107 3

Oxidative stress-induced vascular endothelial cell dysfunction serves an essential role in the initiation and development of atherosclerosis. Sulforaphane (SFN), a naturally occurring antioxidant, has previously demonstrated to exert protective effects on the endothelium against oxidative stress. However, further studies are required to determine its underlying molecular mechanism prior to clinical application. Accumulating evidence suggests that alterations in the microRNA (miRNA/miR)-34a/sirtu ...[more]

PMID: 33488795

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Project description:BackgroundIntervertebral disc degeneration (IDD) is a major contributor to lower back pain, however, the molecular and pathogenetic mechanisms underlying IDD are poorly understood. As a high-risk factor for IDD, compression stress was reported to induce apoptosis of nucleus pulposus (NP) cells and extracellular matrix (ECM) degradation during IDD progression. Circular RNA (circRNA) is a class of endogenous non-coding RNA (ncRNA) and has been reported to function in several diseases. However, whether and how circRNA regulates compression-induced damage of NP cells remains vague. Here, we aimed to investigate the key role of circRNA in compression loading-induced IDD.MethodsWe analysed the circRNA expression of three samples from compression-treated NP cells and three control samples using circRNA microarray assays and further investigated the circRNA involved in compression-induced damage of NP cells (circRNA-CIDN). We investigated the effects of circRNA-CIDN on compression-induced cell apoptosis and NP ECM degradation in vitro and ex vivo. We observed that circRNA-CIDN bound to miRNAs as a miRNA sponge based on luciferase and RNA immunoprecipitation (RIP) assays.FindingsCircRNA-CIDN was significantly downregulated in compression-treated human NP cells, as validated by circRNA microarray and qRT-PCR analysis, and overexpressing circRNA-CIDN inhibited compression-induced apoptosis and NP ECM degradation. Further studies demonstrated that circRNA-CIDN served as a sponge for miR-34a-5p, an important miRNA that enhanced compression-induced damage of NP cells via repressing the silent mating type information regulation 2 homolog 1 (SIRT1). CircRNA-CIDN was also verified to contain IDD development in an ex vivo IDD model.InterpretationOur results revealed that circRNA-CIDN binding to miR-34a-5p played an important role in mitigating compression loading-induced nucleus pulposus cell damage via targeting SIRT1, providing a potential therapeutic strategy for IDD treatment.FundingNational Natural Science Foundation of China (81772391, 81974348), Fundamental Research Funds for the Central Universities (2017KFYXJJ248).

Dataset Information

Sulforaphane protects human umbilical vein endothelial cells from oxidative stress via the miR-34a/SIRT1 axis by upregulating nuclear factor erythroid-2-related factor 2.

Publications

Sulforaphane protects human umbilical vein endothelial cells from oxidative stress via the miR-34a/SIRT1 axis by upregulating nuclear factor erythroid-2-related factor 2.

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