SNX3 mediates heart failure by interacting with HMGB1 and subsequently facilitating its nuclear-cytoplasmic translocation  

作　　者：Hong Li Ming-xia Peng Rui-xue Yang Jian-xing Chen Yue-mei Wang Pan-xia Wang Yue-huai Hu Di-yi Pan Pei-qing Liu Jing Lu 

机构地区：[1]National and Local United Engineering Lab of Druggability and New Drugs Evaluation,Guangdong Provincial Key Laboratory of New Drug Design and Evaluation,Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou,510006,China [2]Department of Biochemistry and Molecular Biology,School of Basic Medical Sciences,Guangzhou University of Chinese Medicine,Guangzhou,510006,China [3]The Research Center of Basic Integrative Medicine,School of Basic Medical Sciences,Guangzhou University of Chinese Medicine,Guangzhou,510006,China [4]Department of Pharmacy,The Third Affiliated Hospital of Guangzhou University of Chinese Medicine,Guangzhou,510378,China

出　　处：《Acta Pharmacologica Sinica》2025年第4期964-975,共12页中国药理学报(英文版)

基　　金：supported by the National Natural Science Foundation of China(82473914,82173808,U21A20419,81903606);Guangzhou Basic and Applied Basic Research Project(2024A04J10013,202102021272);Guangdong Provincial Key Laboratory of Construction Foundation(2017B030314030);Traditional Chinese Medicine Bureau of Guangdong Province(20231134,20231158).

摘　　要：Sorting nexins(SNXs)as the key regulators of sorting cargo proteins are involved in diverse diseases.SNXs can form the specific reverse vesicle transport complex(SNXs-retromer)with vacuolar protein sortings(VPSs)to sort and modulate recovery and degradation of cargo proteins.Our previous study has shown that SNX3-retromer promotes both STAT3 activation and nuclear translocation in cardiomyocytes,suggesting that SNX3 might be a critical regulator in the heart.In this study we investigated the role of SNX3 in the development of pathological cardiac hypertrophy and heart failure.We generated abdominal aortic constriction(AAC)rat model and transverse aortic constriction(TAC)mouse model;hypertrophic neonatal rat cardiomyocytes(NRCMs)were induced by exposure to isoproterenol(10μM).We showed that the expression of SNX3 was significantly upregulated in ISO-treated NRCMs and in the failing heart of AAC rats.Overexpression of SNX3 by intramyocardial injection of Ad-SNX3 induced heart failure in rats,and increased the susceptibility of NRCMs to ISO-induced myocardial injury in vitro.In contrast,conditional knockout of SNX3 in cardiac tissue in mice rescued the detrimental heart function in TAC mice,and knockdown of SNX3 protected against ISO-induced injury in NRCMs and AAC rats.We then conducted immunoprecipitation-based mass spectrometry and localized surface plasmon resonance,and demonstrated a direct interaction between SNX3-retromer and high mobility group box 1(HMGB1),which mediated the efflux of nuclear HMGB1.Moreover,overexpression of HMGB1 in NRCMs inhibited the pro-hypertrophic effects of SNX3,whereas knockdown of HMGB1 abolished the protective effect of SNX3-deficiency.These results suggest that HMGB1 might be a direct cargo protein of SNX3-retromer,and its interaction with SNX3 promotes its efflux from the nucleus,leading to the pathological development of heart failure.

关 键 词：heart failure cardiac hypertrophy SNX3 HMGB1 RETROMER ISOPROTERENOL 

分 类 号：R541.6[医药卫生—心血管疾病]