Extracellular vesicles from hypoxia-preconditioned mesenchymal stem cells alleviates myocardial injury by targeting thioredoxininteracting protein-mediated hypoxia-inducible factor-1αpathway  

作　　者：Cheng-Yu Mao Tian-Tian Zhang Dong-Jiu Li En Zhou Yu-Qi Fan Qing He Chang-Qian Wang Jun-Feng Zhang 

机构地区：[1]Department of Cardiology,Shanghai Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200010,China

出　　处：《World Journal of Stem Cells》2022年第2期183-199,共17页世界干细胞杂志（英文版）（电子版）

基　　金：Supported by National Natural Science Foundation of China,No. 81870264 and No. 81470546;the Shanghai Committee of Science and Technology,No. 18411950500;the Major Disease Joint Project of Shanghai Health System,No. 2014ZYJB0501;Talent Cultivation Project of The Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,No. JC202005

摘　　要：BACKGROUND Extracellular vesicles(EVs)derived from hypoxia-preconditioned(HP)mesenchymal stem cells(MSCs)have better cardioprotective effects against myocardial infarction(MI)in the early stage than EVs isolated from normoxic(NC)-MSCs.However,the cardioprotective mechanisms of HP-EVs are not fully understood.AIM To explore the cardioprotective mechanism of EVs derived from HP MSCs.METHODS We evaluated the cardioprotective effects of HP-EVs or NC-EVs from mouse adipose-derived MSCs(ADSCs)following hypoxia in vitro or MI in vivo,in order to improve the survival of cardiomyocytes(CMs)and restore cardiac function.The degree of CM apoptosis in each group was assessed by the terminal deoxynucleotidyl transferase dUTP nick end-labeling and Annexin V/PI assays.MicroRNA(miRNA)sequencing was used to investigate the functional RNA diversity between HP-EVs and NC-EVs from mouse ADSCs.The molecular mechanism of EVs in mediating thioredoxin-interacting protein(TXNIP)was verified by the dual-luciferase reporter assay.Co-immunoprecipitation,western blotting,and immunofluorescence were performed to determine if TXNIP is involved in hypoxia-inducible factor-1 alpha(HIF-1α)ubiquitination and degradation via the chromosomal region maintenance-1(CRM-1)-dependent nuclear transport pathway.RESULTS HP-EVs derived from MSCs reduced both infarct size(necrosis area)and apoptotic degree to a greater extent than NC-EVs from CMs subjected to hypoxia in vitro and mice with MI in vivo.Sequencing of EV-associated miRNAs showed the upregulation of 10 miRNAs predicted to bind TXNIP,an oxidative stress-associated protein.We showed miRNA224-5p,the most upregulated miRNA in HP-EVs,directly combined the 3’untranslated region of TXNIP and demonstrated its critical protective role against hypoxia-mediated CM injury.Our results demonstrated that MI triggered TXNIP-mediated HIF-1αubiquitination and degradation in the CRM-1-mediated nuclear transport pathway in CMs,which led to aggravated injury and hypoxia tolerance in CMs in the early stage of MI.CON

关 键 词：Extracellular vesicles Myocardial infarction Mesenchymal stem cells Hypoxia preconditioning Thioredoxin-interacting protein Hypoxia-inducible factor 1 alpha 

分 类 号：R542.22[医药卫生—心血管疾病]