GSK3β 通过调节 OMA1/PGC1α 通路在高血压加剧动脉粥样硬化中的作用。

IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Hongjia Bao, Changyuan Wang, Yue Jin, Qiang Meng, Jingjing Wu, Qi Liu, Huijun Sun
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引用次数: 0

摘要

动脉粥样硬化与内皮功能障碍和高血压密切相关。GSK3β 是动脉粥样硬化的关键调节因子。本研究旨在探讨 GSK3β 在体外和体内对高血压加剧动脉粥样硬化的影响。本研究使用 L-NAME + HFD-ApoE-/- 小鼠进行为期 12 周的研究,并分析其内皮功能障碍和炎症。油红 O 和 H&E 染色显示,用 GSK3β 抑制剂氯化锂治疗可减少动脉粥样硬化病变和脂质积累。服用氯化锂后,脂质稳态和氧化应激水平均有所降低。经氯化锂处理的载脂蛋白E-/-小鼠血压降低。与 HFD + L-NAME 诱导的小鼠和 oxLDL + L-NAME 处理的人主动脉内皮细胞系(HAECs)相比,氯化锂还抑制了 Drp1、Bax、ICAM1、VCAM1 和 TNF-α 的表达。氯化锂处理增加了MFN2和Bcl2的表达。Mitotracker-red、MitoSOX和JC-1染色表明,与oxLDL + L-NAME处理的HAECs相比,氯化锂处理减少了线粒体分裂和ROS产生,增加了线粒体ΔΨm。氯化锂处理降低了 OMA1 的表达,而增加了 PGC1α 的表达。在 HAECs 中,我们发现敲除 OMA1 增加了线粒体功能和 PGC1α 的表达。与对照组相比,我们还发现氯化锂增加了 OMA1 泛素化,从而降低了 OMA1 的表达。此外,siOMA1还能拮抗ICAM1、VCAM1、TNF-α、Bax和Drp1的蛋白表达,降低Bcl2和MFN2的蛋白表达。综上所述,我们证明了 GSK3β 可通过调节 OMA1/PGC1α 通路和抑制线粒体功能,在高血压加重动脉粥样硬化的过程中起到促进作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The contributory role of GSK3β in hypertension exacerbating atherosclerosis by regulating the OMA1/PGC1α pathway.

Atherosclerosis is closely related to endothelial dysfunction and hypertension. GSK3β is a critical regulator in atherosclerosis. This study was carried out to investigate the effects of GSK3β on hypertension exacerbating atherosclerosis in vitro and in vivo. L-NAME + HFD-ApoE-/- mice were used for this study for 12 weeks, and their endothelial dysfunction and inflammation were analyzed. Oil red O and H&E staining revealed that treatment with LiCl, an inhibitor of GSK3β, reduced atherosclerotic lesions and lipid accumulation. The levels of lipid homeostasis and oxidation stress were attenuated following LiCl administration. LiCl-treated ApoE-/- mice showed lowered blood pressure. LiCl also suppressed the expressions of Drp1, Bax, ICAM1, VCAM1 and TNF-α compared to HFD + L-NAME induced mice and oxLDL + L-NAME-treated Human aorta endothelial cell line(HAECs). LiCl treatment increased the expressions of MFN2 and Bcl2. Mitotracker-red, MitoSOX and JC-1 staining indicated that LiCl treatment reduced mitochondrial division and ROS production, increased mitochondrial ΔΨm compared to oxLDL + L-NAME-treated HAECs. The expression of OMA1 was decreased by LiCl treatment, while PGC1α expression was increased. In HAECs, we found that OMA1 knockdown increased mitochondrial function and the expression of PGC1α. We also demonstrated LiCl increased OMA1 ubiquitination compared with the Control group, thus decreased OMA1 expression. Furthermore, siOMA1 antagonized the increased protein expressions of ICAM1, VCAM1, TNF-α, Bax and Drp1, decreased the protein expressions of Bcl2 and MFN2 by siPGC1α. Taken together, we demonstrated that GSK3β could play a contributory role in hypertension exacerbating atherosclerosis by regulating the OMA1/PGC1α pathway and inhibiting mitochondrial function.

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来源期刊
Apoptosis
Apoptosis 生物-生化与分子生物学
CiteScore
9.10
自引率
4.20%
发文量
85
审稿时长
1 months
期刊介绍: Apoptosis, a monthly international peer-reviewed journal, focuses on the rapid publication of innovative investigations into programmed cell death. The journal aims to stimulate research on the mechanisms and role of apoptosis in various human diseases, such as cancer, autoimmune disease, viral infection, AIDS, cardiovascular disease, neurodegenerative disorders, osteoporosis, and aging. The Editor-In-Chief acknowledges the importance of advancing clinical therapies for apoptosis-related diseases. Apoptosis considers Original Articles, Reviews, Short Communications, Letters to the Editor, and Book Reviews for publication.
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