An Autophagy-Associated MITF-GAS5-miR-23 Loop Attenuates Vascular Oxidative and Inflammatory Damage in Sepsis

作者全名："Cheng, Junning; Ding, Chang; Tang, Huying; Zhou, Haonan; Wu, Mingdong; Chen, Yikuan"

作者地址："[Cheng, Junning; Zhou, Haonan; Wu, Mingdong; Chen, Yikuan] Chongqing Med Univ, Dept Vasc Surg, Affiliated Hosp 2, Chongqing 400010, Peoples R China; [Cheng, Junning; Ding, Chang; Tang, Huying] Chongqing Med Univ, Cent Lab Sch Life Sci, Chongqing 400016, Peoples R China; [Ding, Chang] Chongqing Tradit Chinese Med Hosp, Dept Ultrasound, Chongqing 400013, Peoples R China; [Tang, Huying] Army Mil Med Univ, Mil Med Univ 3, Southwest Hosp, Dept Radiol, Chongqing 400038, Peoples R China"

通信作者："Chen, YK (通讯作者)，Chongqing Med Univ, Dept Vasc Surg, Affiliated Hosp 2, Chongqing 400010, Peoples R China."

来源：BIOMEDICINES

ESI学科分类：　

WOS号：WOS:001037880300001

JCR分区：Q1

影响因子：3.9

年份：2023

卷号：11

期号：7

开始页：　

结束页：　

文献类型：Article

关键词：sepsis; oxidative stress; inflammation; MiT-TFE transcription factor; autophagy

摘要："Background: Sepsis induces GAS5 expression in the vascular endothelium, but the molecular mechanism is unclear, as is the role of GAS5 in sepsis. Methods and results: We observed that GAS5 expression in the endothelium was significantly upregulated in a sepsis mouse model. ChIP-PCR and EMSA confirmed that the oxidative stress (OS)-activated MiT-TFE transcription factor (MITF, TFE3, and TFEB)-mediated GAS5 transcription. In vitro, GAS5 overexpression attenuated OS and inflammation in endothelial cells (ECs) while maintaining the structural and functional integrity of mitochondria. In vivo, GAS5 reduced tissue ROS levels, maintained vascular barrier function to reduce leakage, and ultimately attenuated sepsis-induced lung injury. Luciferase reporter assays revealed that GAS5 protected MITF from degradation by sponging miR-23, thereby forming a positive feedback loop consisting of MITF, GAS5, and miR-23. Despite the fact that the OS-activated MITF-GAS5-miR-23 loop boosted MITF-mediated p62 transcription, ECs do not need to increase mitophagy to exert mitochondrial quality control since MITF-mediated Nrf2 transcription exists. Compared to mitophagy, MITF-transcribed p62 prefers to facilitate the autophagic degradation of Keap1 through a direct interaction, thereby relieving the inhibition of Nrf2 by Keap1, indicating that MITF can upregulate Nrf2 at both the transcriptional and posttranscriptional levels. Following this, ChIP-PCR demonstrated that Nrf2 can also transcribe MITF, revealing that there is a reciprocal positive regulatory association between MITF and Nrf2. Conclusion: In sepsis, the ROS-activated MITF-GAS5-miR-23 loop integrated the antioxidant and autophagy systems through MITF-mediated transcription of Nrf2 and p62, which dynamically regulate the level and type of autophagy, as well as exert antioxidant and anti-inflammatory effects."

基金机构：National Natural Science Foundation of China [81470583]; Natural Science Foundation of ChongQing [CSTB2022NSCQ-MSX0805]; Kuanren Talents Program of the second affiliated hospital of Chongqing Medical University

基金资助正文："This research was supported by the National Natural Science Foundation of China (no. 81470583), Natural Science Foundation of ChongQing (CSTB2022NSCQ-MSX0805), and Kuanren Talents Program of the second affiliated hospital of Chongqing Medical University."