NRF2-HIF2α Signaling Attenuates Endothelial Cell Senescence and Maintains Intercellular Junctions in Diabetes.

IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY International Journal of Biological Sciences Pub Date : 2024-07-22 eCollection Date: 2024-01-01 DOI:10.7150/ijbs.96719
Jian Shen, Yifan Lai, Yaner Lu, Yabin Liu, Jinlong Zhang, Yan Wu, Yunan Pan, Haibo Chen, Qiyue Gao, Qucheng Wei, Yuwen Chen, Jian Ye, Yinuo Lin, Bingchen Liu, Jun Jiang, Jinliang Nan
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Abstract

In the context of diabetes, endothelial cells frequently exhibit compromised intercellular junctions and accelerated cellular senescence simultaneously. The precise mechanisms underlying these issues and the identification of effective treatments remain largely undefined. Our findings reveal that human umbilical vein endothelial cells (HUVECs) can counteract senescence and uphold the integrity of intercellular junctions under mildly to moderately elevated glucose levels (10 mM and 15 mM) via two primary mechanisms: i) The acetylation of NRF2 at lysine residues K56, K68, and K52 prevents its ubiquitination, enhancing the transcription of antioxidant genes GST, SOD1, and GPX1. This activity diminishes cytoplasmic oxidative stress, thereby mitigating endothelial cell senescence. ii) The interaction between the Neh2 domain of NRF2 and the PAS-B domain of HIF-2α within the nucleus curtails the attachment of HIF-2α to the NOX4/p22phox promoter. This action lessens oxidative stress near the cell membrane, maintaining intercellular junctions by safeguarding the disulfide bonds in occludin and E-cadherin from disruption. However, these protective strategies prove insufficient under severe hyperglycemic conditions (25 mM). Further investigation has identified Oltipraz, an activator of NRF2, as also promoting the degradation of HIF-2α. Through its simultaneous modulation of NRF2 and HIF-2α, Oltipraz significantly reduces cellular senescence and prevents the deterioration of intercellular junctions in HUVECs subjected to high glucose concentrations (25 mM). Our research positions Oltipraz as a promising therapeutic candidate for mitigating diabetes-induced vascular endothelial damage, potentially offering benefits against diabetes-related atherosclerosis and valvular calcification.

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NRF2-HIF2α信号传导可减轻糖尿病内皮细胞衰老并维持细胞间连接
在糖尿病的情况下,内皮细胞经常同时表现出细胞间连接受损和细胞衰老加速。这些问题的确切机制和有效治疗方法在很大程度上仍未确定。我们的研究结果表明,人脐静脉内皮细胞(HUVECs)能在轻度至中度升高的葡萄糖水平(10 毫摩尔和 15 毫摩尔)下通过两种主要机制抵御衰老并维护细胞间连接的完整性:i) NRF2 在赖氨酸残基 K56、K68 和 K52 上的乙酰化能阻止其泛素化,从而增强抗氧化基因 GST、SOD1 和 GPX1 的转录。ii) NRF2 的 Neh2 结构域与细胞核内 HIF-2α 的 PAS-B 结构域之间的相互作用抑制了 HIF-2α 与 NOX4/p22phox 启动子的连接。这一作用减轻了细胞膜附近的氧化应激,并通过保护闭锁素和 E-cadherin 中的二硫键不被破坏来维持细胞间的连接。然而,在严重的高血糖条件下(25 毫摩尔),这些保护策略被证明是不够的。进一步的研究发现,NRF2 的激活剂 Oltipraz 也能促进 HIF-2α 的降解。通过同时调节 NRF2 和 HIF-2α,Oltipraz 在高浓度葡萄糖(25 mM)条件下可显著减少细胞衰老,并防止 HUVEC 细胞间连接的恶化。我们的研究将Oltipraz定位为减轻糖尿病诱导的血管内皮损伤的一种有希望的候选疗法,它可能对糖尿病相关的动脉粥样硬化和瓣膜钙化有益。
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来源期刊
International Journal of Biological Sciences
International Journal of Biological Sciences 生物-生化与分子生物学
CiteScore
16.90
自引率
1.10%
发文量
413
审稿时长
1 months
期刊介绍: The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.
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