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

查看全文 作　　者：Xuesong [1]Li;Xiang [1]Chen;Longbin [1,2]Zheng;Minghong [1]Chen;Yunjia [1]Zhang;Ruigong [1]Zhu;Jiajing [3]Chen;Jiaming [1]Gu;Quanwen [1]Yin;Hong [1]Jiang;Xuan [1]Wu;Xian [1]Ji;Xin [1]Tang;Mengdie [1]Dong;Qingguo [4]Li;Yuanqing [1]Gao;Hongshan [1,4,5,6]Chen

机构地区：[1]Key Laboratory of Cardiovascular and Cerebrovascular Medicine,School of Pharmacy,Nanjing Medical University,Nanjing 211166,China;[2]Department of Anesthesiology,Sir Run Run Hospital,Nanjing Medical University,Nanjing 211166,China;[3]Department of Pharmacy,Huashan Hospital,Fudan University,Shanghai 200040,China;[4]Department of Cardiothoracic Surgery,the Second Affliated Hospital of Nanjing Medical University,Nanjing 211166,China;[5]Key Laboratory of Targeted Intervention of Cardiovascular Disease,Collaborative Innovation Center for Cardiovascular Disease Translational Medicine,Nanjing Medical University,Nanjing 211166,China;[6]Department of Cardiology,Huai'an First People's Hospital Affliated with Nanjing Medical University,Huai'an 223399,China

出　　处：《Acta Pharmaceutica Sinica B》索引2023年第13卷第12期,共20页

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). 摘　　要：Inflammation-driven endothelial dysfunction is the major initiating factor in atherosclerosis,while the underlying mechanism remains elusive.Here,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 arteries.Typically,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 infammation.In 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 process.Endothelium-specific STING and BRD4 deficiency significantly decreased the plaque area and inflammation.Mechanistically,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 stimulation.Especially,compared to macrophages,endothelial STING activation plays a more pronounced role in atherosclerosis.We 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. 关键词：Endothelial dysfunction Infiammation Mitochondrial DNA STING ROS PERK BRD4 ATHEROSCLEROSIS

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

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