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.

中文翻译：

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TXNIP通过增强TGFB1/Smad3通路并促进NLRP3炎性体激活，加重小鼠心肌梗死后的心脏纤维化和功能障碍。

心肌梗塞（MI）导致高死亡率。心肌梗死后纤维化疤痕组织的大小是心肌梗死结果的独立预测因素。硫氧还蛋白相互作用蛋白（TXNIP）参与多种纤维化疾病。然而，其在心肌梗死后心脏纤维化中的作用仍知之甚少。在本研究中，我们使用野生型（WT）、Txnip-knockout（Txnip-KO）型和Txnip-knock-in小鼠MI模型研究了TXNIP在MI后心脏纤维化中的生物学作用及其潜在机制(Txnip-KI) 型。MI后，动物的TXNIP水平显着上调，纤维化面积显着扩大，心脏功能明显受损。这些变化在 Txnip-KI 条件下进一步加剧，但在 Txnip-KO 动物中得到改善。MI 还会导致纤维化指数 I 型胶原蛋白、III 型胶原蛋白、肌动蛋白 α 2 (ACTA2) 和结缔组织生长因子 (CTGF) 的蛋白质水平升高。Txnip-KI 组的这些蛋白质水平最高，而 Txnip-KO 小鼠的水平最低。此外，Txnip-KI 在治疗后显着上调转化生长因子 (TGF)B1、p-Smad3、NOD-、LRR- 和pyrin 结构域蛋白 3 (NLRP3)、Cleaved Caspase-1 和白细胞介素 (IL)1B 的水平MI，但这些影响被 Txnip-KO 显着抵消。此外，MI后，Smad7水平显着下降，特别是在Txnip-KI小鼠中。TXNIP 可能通过激活 NLRP3 炎性体、随后产生 IL1B、然后增强 TGFB1/Smad3 通路，从而加剧 MI 后纤维化和心功能障碍的进展。因此，TXNIP 可能作为治疗 MI 后心脏纤维化的新的潜在治疗靶点。