Autophagy enhanced by curcumin ameliorates inflammation in atherogenesis via the TFEB-P300-BRD4 axis  

作　　者：Xuesong Li Ruigong Zhu Hong Jiang Quanwen Yin Jiaming Gu Jiajing Chen Xian Ji Xuan Wu Haiping Fu Hui Wang Xin Tang Yuanqing Gao Bingjian Wang Yong Ji Hongshan Chen 

机构地区：[1]Key Laboratory of Cardiovascular and Cerebrovascular Medicine,School of Pharmacy,Nanjing Medical University,Nanjing 211166,China [2]Key Laboratory of Targeted Intervention of Cardiovascular Disease,Collaborative Innovation Center for Cardiovascular Disease Translational Medicine,Nanjing Medical University,Nanjing 211166,China [3]Department of Cardiothoracic Surgery,the Second Affiliated Hospital of Nanjing Medical University,Nanjing 211166,China [4]Department of Cardiology,Huai’an First People’s Hospital Affiliated with Nanjing Medical University,Huai’an 223399,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第5期2280-2299,共20页药学学报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China (31771334,81970428 and 81800385);the Key Research Plan of the National Natural Science Foundation of China (81820108002);the Major Research Plan of the National Natural Science Foundation of China (91649125 and 91639204);University Natural Science Research of Jiangsu Province (18KJB310008,China);Jiangsu Province Health and Family Planning Commission Scientific Research Project (H2017011,China);Jiangsu Provincial Medical Youth Talent (QNRC2016432,China);Top Talents Project Foundation of “Six-One Project” for High-level Health Talents of Jiangsu Province (LGY2020055,China);Technology Development Foundation of Nanjing Medical University (2017NJMUZD020,China);supported by the program of special professor of Jiangsu Province,the program of the special medical experts of Jiangsu Province and the program of innovation and entrepreneurship team plan of Jiangsu Province,China。

摘　　要：Disturbance of macrophage-associated lipid metabolism plays a key role in atherosclerosis.Crosstalk between autophagy deficiency and inflammation response in foam cells(FCs) through epigenetic regulation is still poorly understood. Here, we demonstrate that in macrophages, oxidized lowdensity lipoprotein(ox-LDL) leads to abnormal crosstalk between autophagy and inflammation,thereby causing aberrant lipid metabolism mediated through a dysfunctional transcription factor EB (TFEB)-P300-bromodomain-containing protein 4(BRD4) axis. ox-LDL led to macrophage autophagy deficiency along with TFEB cytoplasmic accumulation and increased reactive oxygen species generation. This activated P300 promoted BRD4 binding on the promoter regions of inflammatory genes, consequently contributing to inflammation with atherogenesis. Particularly, ox-LDL activated BRD4-dependent super-enhancer associated with liquid-liquid phase separation(LLPS) on the regulatory regions of inflammatory genes. Curcumin(Cur) prominently restored FCs autophagy by promoting TFEB nuclear translocation, optimizing lipid catabolism, and reducing inflammation. The consequences of P300 and BRD4 on super-enhancer formation and inflammatory response in FCs could be prevented by Cur. Furthermore, the anti-atherogenesis effect of Cur was inhibited by macrophage-specific Brd4 overexpression or Tfeb knock-out in Apoe knock-out mice via bone marrow transplantation. The findings identify a novel TFEB-P300-BRD4 axis and establish a new epigenetic paradigm by which Cur regulates autophagy, inhibits inflammation, and decreases lipid content.

关 键 词：MACROPHAGE AUTOPHAGY TFEB P300 BRD4 INFLAMMATION Atherosclerosis CURCUMIN 

分 类 号：R285[医药卫生—中药学]