SIRT3激活剂灵芝酸D通过NRF2/GPX4途径调节气道粘蛋白MUC5AC的表达。

The SIRT3 activator ganoderic acid D regulates airway mucin MUC5AC expression via the NRF2/GPX4 pathway.

作者信息

Wang Jiancheng, Li Jiayao, He Yingying, Huang Xiaochun, Feng Jianguo, Liu Li, Liu Yulin, Jiang Xian, Jia Jing

机构信息

Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China; Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China.

Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China.

出版信息

Pulm Pharmacol Ther. 2023 Dec;83:102262. doi: 10.1016/j.pupt.2023.102262. Epub 2023 Oct 23.

DOI:10.1016/j.pupt.2023.102262

PMID:37879430

Abstract

PURPOSE

The expression of MUC5AC, a highly prevalent airway mucin, is regulated by stimulatory factors such as oxidative stress. Ganoderic acid D (GAD) activates mitochondrial deacetylase SIRT3. SIRT3 regulates mitochondrial function through deacetylation of mitochondrial proteins, thereby playing a significant role in alleviating oxidative stress-related diseases. Therefore, this study aimed to investigate the mechanisms and rationale underlying the regulation of MUC5AC expression by GAD.

METHODS

Human airway epithelial cells (NCI-H292) were exposed to pyocyanin (PCN) to establish an in vitro cell model of airway mucus hypersecretion. The expression of SIRT3, MUC5AC, and NRF2 pathway proteins in cells was assessed. Cellular mitochondrial morphology and oxidative stress markers were analyzed. C57BL/6 mice were induced with Pseudomonas aeruginosa (PA) to establish an in vivo mouse model of airway mucus hypersecretion. The expression of SIRT3 and MUC5AC in the airways was examined. In addition, the differential expression of target genes in the airway epithelial tissues of patients with chronic obstructive pulmonary disease (COPD) was analyzed using publicly available databases.

RESULTS

The results revealed a significant upregulation of MUC5AC expression and a significant downregulation of SIRT3 expression in relation to airway mucus hypersecretion. GAD inhibited the overexpression of MUC5AC in PCN-induced NCI-H292 cells and PA-induced mouse airways by upregulating SIRT3. GAD activated the NRF2/GPX4 pathway and inhibited PCN-induced oxidative stress and mitochondrial morphological changes in NCI-H292 cells. However, ML385 inhibited the regulatory effects of GAD on MUC5AC expression.

CONCLUSION

The SIRT3 activator GAD downregulated MUC5AC expression, potentially through activation of the NRF2/GPX4 pathway. Accordingly, GAD may be a potential treatment approach for airway mucus hypersecretions.

摘要

目的

MUC5AC是一种高度普遍存在的气道黏蛋白，其表达受氧化应激等刺激因素调控。灵芝酸D（GAD）可激活线粒体去乙酰化酶SIRT3。SIRT3通过使线粒体蛋白去乙酰化来调节线粒体功能，从而在减轻氧化应激相关疾病中发挥重要作用。因此，本研究旨在探讨GAD调节MUC5AC表达的机制及原理。

方法

将人气道上皮细胞（NCI-H292）暴露于绿脓菌素（PCN）中，以建立气道黏液高分泌的体外细胞模型。评估细胞中SIRT3、MUC5AC和NRF2通路蛋白的表达。分析细胞线粒体形态和氧化应激标志物。用铜绿假单胞菌（PA）诱导C57BL/6小鼠，以建立气道黏液高分泌的体内小鼠模型。检测气道中SIRT3和MUC5AC的表达。此外，利用公开可用数据库分析慢性阻塞性肺疾病（COPD）患者气道上皮组织中靶基因的差异表达。

结果

结果显示，与气道黏液高分泌相关的MUC5AC表达显著上调，SIRT3表达显著下调。GAD通过上调SIRT3抑制PCN诱导的NCI-H292细胞和PA诱导的小鼠气道中MUC5AC的过表达。GAD激活NRF2/GPX4通路，并抑制PCN诱导的NCI-H292细胞中的氧化应激和线粒体形态变化。然而，ML385抑制了GAD对MUC5AC表达的调节作用。