TRIM44 aggravates cardiac fibrosis after myocardial infarction via TAK1 stabilization

Myocardial infarction (MI) is one of the most dangerous cardiovascular events. Cardiac fibrosis is a common pathological feature of remodeling after injury that is related to adverse clinical results with no effective treatment. Previous studies have confirmed that TRIM44, an E3 ligase, can promote the proliferation and migration of various tumor cells. However, the role of TRIM44 in cardiac fibrosis remains unknown. Models of TGF-& beta;1 stimulation and MI-induced fibrosis were established to investigate the role and potential underlying mechanism of TRIM44 in cardiac fibrosis. The results showed that cardiac fibrosis was significantly inhibited after TRIM44 knockdown in a mouse model of MI, while it was enhanced when TRIM44 was overexpressed. Furthermore, in vitro studies showed that fibrosis markers were significantly reduced in cardiac fibroblasts (CFs) with TRIM44 knockdown, whereas TRIM44 overexpression promoted the expression of fibrosis markers. Mechanistically, TRIM44 maintains TAK1 stability by inhibiting the degradation of k48-linked poly-ubiquitination-mediated ubiquitination, thereby increasing phosphorylated TAK1 expression in the fibrotic environment and activating MAPKs to promote fibrosis. Pharmacological inhibition of TAK1 phosphorylation reversed the fibrogenic effects of TRIM44 overexpression. Combined, these results suggest that TRIM44 is a potential therapeutic target for cardiac fibrosis.

Automated summary

Myocardial infarction (MI) is a dangerous cardiovascular event with no effective treatment for cardiac fibrosis, a common feature of remodeling after injury. TRIM44, an E3 ligase, has been shown to promote tumor cell proliferation and migration, but its role in cardiac fibrosis is unknown. In this study, the role of TRIM44 in cardiac fibrosis was investigated using stimulation by TGF-β1 and MI-induced fibrosis models. The results showed that TRIM44 knockdown inhibited cardiac fibrosis in a mouse model of MI, while TRIM44 overexpression enhanced fibrosis. Mechanistically, TRIM44 maintained TAK1 stability by inhibiting degradation, increasing phosphorylated TAK1 expression, activating MAPKs, and promoting fibrosis. Pharmacological inhibition of TAK1 phosphorylation reversed the fibrogenic effects of TRIM44 overexpression. These findings suggest that TRIM44 may be a potential therapeutic target for cardiac fibrosis.