丹参酮IIA调节Sirt5和Metll3相互作用，调控冠状动脉微血管损伤中线粒体-内质网未折叠蛋白的反应

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-06-16 DOI:10.1016/j.phymed.2025.156982

Xiangyi Pu , Qiaomin Wu , Zhaoqi Yan , Siyuan Zhou, Qin Zhang, Xinai Zhang, Yongyuan Cai, Zhiming Liu, Ruxiu Liu, Xing Chang

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引用次数: 0

摘要

背景中药在治疗冠状动脉微血管损伤方面具有显著优势，为心血管疾病的治疗提供了新的策略。其中，丹参酮IIA （TS）具有调节线粒体和内质网（ER）功能的作用。然而，TS发挥其作用的确切机制，特别是通过微血管内皮细胞（MECs）中METTL3-和sirt5介导的未折叠蛋白反应（UPR）途径，仍然知之甚少。本研究旨在阐明SIRT5和METTL3在介导TS对mec线粒体和内质网功能的保护作用中的作用，重点研究UPR通路。研究设计利用心肌细胞特异性敲除和转基因小鼠来研究SIRT5和METTL3的作用。实验组mec经TS处理后，观察各组细胞功能变化。方法采用共聚焦显微镜、电镜、JC-1法、MTT法和分子对接技术对大鼠线粒体和内质网功能进行检测。对关键标志物，包括线粒体膜电位、蛋白表达（PINK1、Parkin、PERK、CHOP和Nrf-1）和转录水平（PGC1-α、TFAM和ATF5）进行量化。钙离子水平和线粒体呼吸功能也被评估。结果sts治疗增强了线粒体稳定性，恢复了线粒体膜电位，并通过METTL3-和sirt5介导的UPR途径调节钙超载。它上调保护蛋白（PGC1-α、TFAM和Nrf-1），同时降低氧化应激和内质网应激标志物（CHOP、PERK和ATF5）。分子对接证实了SIRT5和METTL3之间的直接相互作用。这些变化共同减轻了微血管内皮损伤和线粒体生物发生的正常化。结论ts通过稳定线粒体功能、减轻钙超载、通过METTL3和SIRT5调节UPR信号通路对mec具有保护作用。

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Tanshinone IIA modulates Sirt5 and Metll3 interaction to govern mitochondria-endoplasmic reticulum unfolded protein response in coronary microvascular injury

Background

Traditional Chinese medicine (TCM) has demonstrated significant advantages in the treatment of coronary microvascular injury, offering novel therapeutic strategies for cardiovascular diseases. Among its active compounds, Tanshinone IIA (TS) has been shown to regulate mitochondrial and endoplasmic reticulum (ER) function. However, the precise mechanisms through which TS exerts its effects, particularly via METTL3- and SIRT5-mediated unfolded protein response (UPR) pathways in microvascular endothelial cells (MECs), remain poorly understood.

Purpose

This study aims to elucidate the role of SIRT5 and METTL3 in mediating the protective effects of TS on mitochondrial and ER function in MECs, focusing on the UPR pathways.

Study design

Cardiomyocyte-specific knockout and transgenic mice were utilized to investigate the role of SIRT5 and METTL3. MECs from experimental groups were treated with TS, and various cellular functions were analyzed.

Methods

The study employed confocal microscopy, electron microscopy, JC-1 assay, MTT assay, and molecular docking techniques to assess mitochondrial and ER functions. Key markers, including mitochondrial membrane potential, protein expression (PINK1, Parkin, PERK, CHOP, and Nrf-1), and transcription levels (PGC1-α, TFAM, and ATF5), were quantified. Calcium ion levels and mitochondrial respiratory functions were also evaluated.

Results

TS treatment enhanced mitochondrial stability, restored mitochondrial membrane potential, and regulated calcium overload through METTL3- and SIRT5-mediated UPR pathways. It upregulated protective proteins (PGC1-α, TFAM, and Nrf-1) while reducing oxidative stress and ER stress markers (CHOP, PERK, and ATF5). Molecular docking confirmed a direct interaction between SIRT5 and METTL3. These changes collectively mitigated microvascular endothelial damage and normalized mitochondrial biogenesis.

Conclusion

TS exerts protective effects on MECs by stabilizing mitochondrial function, alleviating calcium overload, and modulating UPR signaling via METTL3 and SIRT5.

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.