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

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.