TRIM21 exacerbates hypoxia-induced cardiomyocyte Pyroptosis through GSDMD ubiquitination in post-myocardial infarction heart failure.

Myocardial cell damage following acute myocardial infarction (MI) plays a critical role in the development of heart failure (HF). Pyroptosis, a form of programmed cell death, is a key mechanism underlying myocardial injury in MI. Although tripartite motif- containing protein 21 (TRIM21) has been implicated in pyroptosis, its role in HF after MI remains unclear. An in vitro model of hypoxic injury in myocardial cells was established using hypoxic culture conditions. In vivo MI model was created by ligating the left anterior descending (LAD) coronary artery in mice, followed by a 28-day recovery period. The role of TRIM21 in cardiomyocyte pyroptosis and subsequent HF after MI was assessed by TRIM21 knockdown and overexpression in cells, as well as selective knockdown in mouse myocardium. Various techniques, including Western blotting, ELISA, lactate dehydrogenase (LDH) activity assays, immunoprecipitation, and immunofluorescence, were used. In mouse models of HF after MI and cellular hypoxia, the expression of TRIM21 and pyroptosis-related proteins was elevated. In vivo experiments showed that TRIM21 knockdown reduced myocardial fibrosis in the acute phase and improved cardiac dysfunction during the healing phase of MI. In vitro studies revealed that hypoxia upregulated TRIM21 expression and enhanced cardiomyocyte pyroptosis by promoting gasdermin D (GSDMD) ubiquitination. Further experiments confirmed that TRIM21 is regulated by HDAC6, which increases cardiomyocyte pyroptosis. Elevated TRIM21 expression post-MI exacerbates GSDMD ubiquitination and promotes cardiomyocyte pyroptosis. TRIM21 knockdown reduces myocardial pyroptosis and improves HF outcomes after MI. These findings suggest that TRIM21 may serve as a potential therapeutic target for HF intervention.