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

• Published in: Acta biochimica et biophysica Sinica Vol. 55; no. 12; pp. 1950 - 1960
• Main Authors: Zhang, Yan, Wang, Jin, Wang, Xuejiao, Li, Aiyun, Lei, Zhandong, Li, Dongxue, Xing, Dehai, Zhang, Yichao, Su, Wanzhen, Jiao, Xiangying
• Format: Journal Article
• Language: English
• Published: China China Science Publishing & Media Ltd 01.10.2023
• Subjects: Animals; cardiac fibrosis; cardiac function; Collagen; Fibrosis; inflammasome; Inflammasomes - metabolism; Mice; Mice, Inbred NOD; Myocardial Infarction; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; thioredoxin-interacting protein; cardiac function; thioredoxin-interacting protein; cardiac fibrosis; inflammasome; myocardial infarction
• ISSN: 1672-9145; 1745-7270
• DOI: 10.3724/abbs.2023150

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), -knockout ( -KO) type and -knock-in ( -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 -KI conditions but are ameliorated in -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 -KI group exhibits the highest levels of these proteins, while the lowest levels are observed in the -KO mice. Furthermore, -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 -KO. In addition, after MI, the Smad7 level significantly decreases, particularly in the -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.