Mitophagy deficiency activates stimulator of interferon genes activation and aggravates pathogenetic cardiac remodeling  

作　　者：Guoxiang Zhou Xiaowen Wang Mingyu Guo Can Qu Lei Gao Jiang Yu Yuanjing Li Suxin Luo Qiong Shi Yongzheng Guo 

机构地区：[1]Division of Cardiology,The First Affliated Hospital of Chongqing Medical University,Chongqing 400016,China [2]Department of Cardiothoracic Surgery,The First Affiliated Hospital of Chongqing Medical University,Chongqing 400016,China [3]Department of Pharmacy,The First Affiliated Hospital of Chongqing Medical University,Chongqing 400016,China [4]The Department of Laboratory Medicine,M.O.E.Key Laboratory of Laboratory Medical Diagnostics,Chongqing Medical University,Chongqing 400016,China

出　　处：《Genes & Diseases》2024年第6期381-394,共14页基因与疾病（英文）

基　　金：supported by grants from the Natural Science Foundation of China (No.82070238);the China Postdoctoral Science Foundation (No.2022M720601);the Natural Science Foundation of Chongqing,China (No.CSTB2022NSCQMSx0913);the Program for Youth Innovation in Future Medicine,Chongqing Medical University (No.W0168);the Science Fund of the First Affiliated Hospital of Chongqing Medical University (No.PYJJ2021-05);the Postdoctoral Incubation Project of The First Affiliated Hospital of Chongqing Medical University (No.CYYY-BSHPYXM-202204)。

摘　　要：Stimulator of interferon genes(STING)has recentlybeen found to play a crucial role in cardiac sterile inflammation and dysfunction.The role of stimulator of interferon genes(STING)in cardiac sterile inflammation and dysfunction has been recently discovered.This study aims to examine the involvement of STING in pathological cardiac remodeling and the mechanisms that govern the activation of the STING pathway.To investigate this,transverse aortic constriction(TAC)was performed on STING knockout mice to induce pressure over-load-induced cardiac remodeling.Subsequently,cardiac function,remodeling,and inflammation levels were evaluated.The STING pathway was found to be activated in the pressure overload-stressed heart and angiotensin II(Ang Il)-stimulated cardiac fibroblasts.Loss of STING expression led to a significant reduction in inflammatory responses,mitochondrial fragmenta-tion,and oxidative stress in the heart,resulting in attenuated cardiac remodeling and dysfunc-tion.Furthermore,the exacerbation of pressure overload-induced sTING-mediated inflammation and pathological cardiac remodeling was observed when mitophagy was sup-pressed through the silencing of Parkin,an E3 ubiquitin ligase.Taken together,these findings indicate that STING represents a newly identified and significant molecule implicated in the process of pathological cardiac remodeling and that mitophagy is an upstream mechanism that regulates STING activation.Targeting STING may therefore provide a novel therapeutic strategy for pathological cardiac remodeling and heart failure.

关 键 词：Cardiac remodeling Mitochondrial autophagy mtDNA Sterile inflammation STING 

分 类 号：R541[医药卫生—心血管疾病]