ASF1A-dependent P300-mediated histone H3 lysine 18 lactylation promotes atherosclerosis by regulating EndMT

作     者：Mengdie Dong Yunjia Zhang Minghong Chen Yongkang Tan Jiao Min Xian He Fuhao Liu Jiaming Gu Hong Jiang Longbin Zheng Jiajing Chen Quanwen Yin Xuesong Li Xiang Chen Yongfeng Shao Yong Ji Hongshan Chen Mengdie Dong;Yunjia Zhang;Minghong Chen;Yongkang Tan;Jiao Min;Xian He;Fuhao Liu;Jiaming Gu;Hong Jiang;Longbin Zheng;Jiajing Chen;Quanwen Yin;Xuesong Li;Xiang Chen;Yongfeng Shao;Yong Ji;Hongshan Chen

作者机构：Department of Cardiovascular Surgerythe First Affiliated Hospital of Nanjing Medical Universityand Key Laboratory of Cardiovascular and Cerebrovascular MedicineSchool of PharmacyNational Vaccine Innovation PlatformNanjing Medical UniversityNanjing 211166China Key Laboratory of Cardiovascular and Cerebrovascular MedicineSchool of PharmacyNanjing Medical UniversityNanjing 211166China Department of Clinical MedicineNanjing Medical University TIANYUAN Honors SchoolNanjing Medical UniversityNanjing 211166China Department of AnesthesiologySir Run Run HospitalNanjing Medical UniversityNanjing 211166China Department of Cardiovascular Surgerythe First Affiliated Hospital of Nanjing Medical UniversityNanjing 211166China Key Laboratory of Cardiovascular and Cerebrovascular MedicineKey Laboratory of Targeted Intervention of Cardiovascular DiseaseCollaborative Innovation Center for Cardiovascular Disease Translational MedicineState Key Laboratory of Reproductive MedicineSchool of Pharmacythe Affiliated Suzhou Hospital of Nanjing Medical UniversityGusu SchoolNanjing Medical UniversityNanjing 211166China National Key Laboratory of Frigid Zone Cardiovascular Diseases(NKLFZCD)Department of Pharmacology(State-Province Key Laboratories of Biomedicine-Pharmaceutics of China)College of PharmacyKey Laboratory of Cardiovascular Medicine Research and Key Laboratory of Myocardial IschemiaChinese Ministry of EducationNHC Key Laboratory of Cell Transplantationthe Central Laboratory of the First Affiliated HospitalHarbin Medical UniversityHarbin 150081China 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 Affiliated with Nanjing Medical UniversityHuai’an 223399China 

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

年 卷 期：2024年第14卷第7期

页      面：3027-3048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 Natural Science Foundation of China(82270421,81970428,31771334,81800385,82270484,82370376,82121001,82030013,and 82241211) Major Research Plan of the National Natural Science Foundation of China(91649125) the National Key R&D Program of China(2019YFA0802704) The major project of Natural Science Foundation of the Jiangsu Higher Education Institution of China(21KJA310006) Jiangsu Provincial Social Development Project(BE2021749,China) Special Program for Top Innovative Talents(NJMUTY20230082,China) 

主　　题：Histone lactylation Atherosclerosis Endothelial-tomesenchymal transition ASF1A SNAI1 Endothelial dysfunction Lactate Epigenetic 

摘      要：Endothelial-to-mesenchymal transition(EndMT)is a key driver of *** glycolysis is increased in the endothelium of atheroprone areas,accompanied by elevated lactate *** lactylation,mediated by lactate,can regulate gene expression and participate in disease ***,whether histone lactylation is involved in atherosclerosis remains ***,we report that lipid peroxidation could lead to EndMT-induced atherosclerosis by increasing lactatedependent histone H3 lysine 18 lactylation(H3K18la)in vitro and in vivo,as well as in atherosclerotic patients’***,the histone chaperone ASF1A was first identified as a cofactor of P300,which precisely regulated the enrichment of H3K18la at the promoter of SNAI1,thereby activating SNAI1 transcription and promoting *** found that deletion of ASF1A inhibited EndMT and improved endothelial *** analysis based on Apoe^(KO)Asf1a^(ECKO) mice in the atherosclerosis model confirmed the involvement of H3K18la in atherosclerosis and found that endotheliumspecific ASF1A deficiency inhibited EndMT and alleviated atherosclerosis *** of glycolysis by pharmacologic inhibition and advanced PROTAC attenuated H3K18la,SNAI1 transcription,and EndMT-induced *** study illustrates precise crosstalk between metabolism and epigenetics via H3K18la by the P300/ASF1A molecular complex during EndMT-induced atherogenesis,which provides emerging therapies for atherosclerosis.