Non-canonical STING-PERK pathway dependent epigenetic regulation of vascular endothelial dysfunction via integrating IRF3 and NF-κB in inflammatory response

作     者：Xuesong Li Xiang Chen Longbin Zheng Minghong Chen Yunjia Zhang Ruigong Zhu Jiajing Chen Jiaming Gu Quanwen Yin Hong Jiang Xuan Wu Xian Ji Xin Tang Mengdie Dong Qingguo Li Yuanqing Gao Hongshan Chen 

作者机构：Key Laboratory of Cardiovascular and Cerebrovascular MedicineSchool of PharmacyNanjing Medical UniversityNanjing 211166China Department of AnesthesiologySir Run Run HospitalNanjing Medical UniversityNanjing 211166China Department of PharmacyHuashan HospitalFudan UniversityShanghai 200040China Department of Cardiothoracic Surgerythe Second Affliated Hospital of Nanjing Medical UniversityNanjing 211166China Key Laboratory of Targeted Intervention of Cardiovascular DiseaseCollaborative Innovation Center for Cardiovascular Disease Translational MedicineNanjing Medical UniversityNanjing 211166China Department of CardiologyHuai'an First People's Hospital Affliated with Nanjing Medical UniversityHuai'an 223399China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2023年第13卷第12期

页      面：4765-4784页

核心收录：

学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学] 

基　　金：supported by the National Nature Science Foundation of China(82270421,81970428,31771334,81800385,82270484,81873654,31800971,and 82170503) the Major Research Plan of the National Natural Science Foundation of China(91649125) University Natural Science Research of Jiangsu Province(18KJB310008,China) Natural Science Foundation of Jiangsu Province(BK20180684,China) supported by the program of special professor of Jiangsu Province the program of the special medical experts of Jiangsu Province the program of innovation and entrepreneurship team plan of Jiangsu Province Major project supported by the Basic Science(Natural Science)Foundation of the Jiangsu Higher Education Institutions,Jiangsu Provincial Social Development Project(BE2021749,China) 

主　　题：Endothelial dysfunction Infiammation Mitochondrial DNA STING ROS PERK BRD4 Atherosclerosis 

摘      要：Inflammation-driven endothelial dysfunction is the major initiating factor in atherosclerosis,while the underlying mechanism remains ***,we report that the non-canonical stimulator of interferon genes(STING)-PKR-like ER kinase(PERK)pathway was significantly activated in both human and mice atherosclerotic ***,STING activation leads to the activation of interferon regulatory factor 3(IRF3)and nuclear factor-kappa B(NF-κB)/p65,thereby facilitating IFN signals and *** contrast,our study reveals the activated non-canonical STING-PERK pathway increases scaffold protein bromodomain protein 4(BRD4)expression,which encourages the formation of super-enhancers on the proximal promoter regions of the proinflammatory cytokines,thereby enabling the transactivation of these cytokines by integrating activated IRF3 and NF-κB via a condensation ***-specific STING and BRD4 deficiency significantly decreased the plaque area and ***,this pathway is triggered by leaked mitochondrial DNA(mtDNA)via mitochondrial permeability transition pore(mPTP),formed by voltage-dependent anion channel 1(VDAC1)oligomer interaction with oxidized mtDNA upon cholesterol oxidation ***,compared to macrophages,endothelial STING activation plays a more pronounced role in *** propose a non-canonical STING-PERK pathway-dependent epigenetic paradigm in atherosclerosis that integrates IRF3,NF-κB and BRD4 in inflammatory responses,which provides emerging therapeutic modalities for vascular endothelial dysfunction.