TXNIP aggravates cardiac fibrosis and dysfunction after myocardial infarction in mice by enhancing the TGFB1/Smad3 pathway and promoting NLRP3 inflammasome activation  

作　　者：Yan Zhang Jin Wang Xuejiao Wang Aiyun Li Zhandong Lei Dongxue Li Dehai Xing Yichao Zhang Wanzhen Su Xiangying Jiao 

机构地区：[1]Key Laboratory of Cellular Physiology(Shanxi Medical University),Ministry of Education,and Department of Physiology,Shanxi Medical University,Taiyuan 030001,China [2]Department of Foreign Languages,Changzhi Medical College,Changzhi 046000,China

出　　处：《Acta Biochimica et Biophysica Sinica》2023年第12期1950-1960,共11页生物化学与生物物理学报（英文版）

基　　金：supported by the grants from the Funds for Shanxi Key Subjects Construction (FSKSC)and Shanxi“1331 Project”Key Subjects Construction and the Applied Basic Research Project of Shanxi Province (Nos.201901D111192 and 202303021211120).

摘　　要：Myocardial infarction(MI)results in high mortality.The size of fibrotic scar tissue following MI is an independent predictor of MI outcomes.Thioredoxin-interacting protein(TXNIP)is involved in various fibrotic diseases.Its role in post-MI cardiac fibrosis,however,remains poorly understood.In the present study,we investigate the biological role of TXNIP in post-MI cardiac fibrosis and the underlying mechanism using mouse MI models of the wild-type(WT),Txnip-knockout(Txnip-KO)type and Txnip-knock-in(Txnip-KI)type.After MI,the animals present with significantly upregulated TXNIP levels,and their fibrotic areas are remarkably expanded with noticeably impaired cardiac function.These changes are further aggravated under Txnip-KI conditions but are ameliorated in Txnip-KO animals.MI also leads to increased protein levels of the fibrosis indices Collagen I,Collagen III,actin alpha 2(ACTA2),and connective tissue growth factor(CTGF).The Txnip-KI group exhibits the highest levels of these proteins,while the lowest levels are observed in the Txnip-KO mice.Furthermore,Txnip-KI significantly upregulates the levels of transforming growth factor(TGF)B1,p-Smad3,NOD-,LRR-and pyrin domain-containing protein 3(NLRP3),Cleaved Caspase-1,and interleukin(IL)1B after MI,but these effects are markedly offset by Txnip-KO.In addition,after MI,the Smad7 level significantly decreases,particularly in the Txnip-KI mice.TXNIP may aggravate the progression of post-MI fibrosis and cardiac dysfunction by activating the NLRP3 inflammasome,followed by IL1B generation and then the enhancement of the TGFB1/Smad3 pathway.As such,TXNIP might serve as a novel potential therapeutic target for the treatment of post-MI cardiac fibrosis.

关 键 词：cardiac fibrosis cardiac function INFLAMMASOME myocardial infarction thioredoxin-interacting protein 

分 类 号：R542.22[医药卫生—心血管疾病]