SIRT3通过PINK1/Parkin信号通路促进线粒体自噬过程，减轻脓毒症诱导的内皮-间质转化和心脏重塑。

SIRT3 attenuates sepsis-induced EndMT and cardiac remodeling by facilitating mitophagy process via PINK1/Parkin signaling.

作者信息

Liu Penghao, Xu Tianhua, Luo Yujun, Meng Jieqiong, Cui Derong, Wang Aizhong

机构信息

Department of Anesthesiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.

Department of Anesthesia, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai 200032, China.

出版信息

Int Immunopharmacol. 2025 Aug 20;164:115377. doi: 10.1016/j.intimp.2025.115377.

DOI:10.1016/j.intimp.2025.115377

PMID:40840139

Abstract

OBJECTIVE

Endothelial-mesenchymal transition (EndMT) is a key contributor to the progression of sepsis-induced myocardial injury (SIMI). Defective mitophagy can result in oxidative stress and mitochondrial dysfunction, both of which play a critical role in EndMT. Sirtuin 3 (SIRT3), a major deacetylase responsible for mitochondrial quality control, has the potential to regulate EndMT, although the exact mechanism remains unclear. Therefore, this study aims to investigate the role of SIRT3 in mediating EndMT and cardiac remodeling during SIMI.

METHODS

Wild-type and SIRT3 knockout mice were induced with lipopolysaccharide (LPS) for 24-h to mimic SIMI. Human cardiac microvascular endothelial cells were treated with LPS for in vitro experiments. Cardiac function was measured by echocardiography. Cardiac fibrosis was determined by Sirus red and Masson's trichrome staining. The expression of endothelial biomarkers and mesenchymal biomarkers was detected using immunofluorescence and western blot to determine EndMT. Mitochondria function and mitophagy were determined by transmission electron microscopy (TEM) and protein biomarkers. The interaction of SIRT3 with PINK1/Parkin was detected by immunoprecipitation (IP) and co-IP.

RESULTS

Following endotoxin exposure, SIRT3 knockout mice exhibited a more severe EndMT phenotype and increased collagen deposition in cardiac tissues, along with mitochondrial dysfunction and impaired mitophagy. Similarly, LPS treatment induced mitochondrial oxidative stress and disrupted mitophagy flux during EndMT in CMECs, effects that were partially rescued by either rapamycin treatment or SIRT3 upregulation. Furthermore, SIRT3 overexpression enhanced deacetylation of the PINK1/Parkin pathway, thereby promoting mitophagy.

CONCLUSION

Our findings suggest that SIRT3 suppresses EndMT-mediated cardiac fibrosis by promoting PINK1/Parkin-dependent mitophagy, offering novel insights for the treatment of SIMI.

摘要

目的

内皮-间充质转化（EndMT）是脓毒症诱导的心肌损伤（SIMI）进展的关键因素。有缺陷的线粒体自噬可导致氧化应激和线粒体功能障碍，二者在EndMT中均起关键作用。沉默调节蛋白3（SIRT3）是负责线粒体质量控制的主要去乙酰化酶，虽确切机制尚不清楚，但它有调节EndMT的潜力。因此，本研究旨在探讨SIRT3在SIMI期间介导EndMT和心脏重塑中的作用。

方法

用脂多糖（LPS）诱导野生型和SIRT3基因敲除小鼠24小时以模拟SIMI。用人心脏微血管内皮细胞进行体外LPS处理实验。通过超声心动图测量心脏功能。用天狼星红和Masson三色染色法测定心脏纤维化。使用免疫荧光和蛋白质印迹法检测内皮生物标志物和间充质生物标志物的表达以确定EndMT。通过透射电子显微镜（TEM）和蛋白质生物标志物测定线粒体功能和线粒体自噬。通过免疫沉淀（IP）和免疫共沉淀（co-IP）检测SIRT3与PINK1/Parkin的相互作用。

结果

内毒素暴露后，SIRT3基因敲除小鼠表现出更严重的EndMT表型，心脏组织中胶原沉积增加，同时伴有线粒体功能障碍和线粒体自噬受损。同样，LPS处理诱导CMECs在EndMT期间出现线粒体氧化应激并破坏线粒体自噬通量，雷帕霉素处理或SIRT3上调可部分挽救这些效应。此外，SIRT3过表达增强了PINK1/Parkin途径的去乙酰化作用，从而促进线粒体自噬。