Suppression of tRF-Glu with antagomir significantly ameliorated TMAO-induced myocardial fibrosis and improved cardiac function in a high-choline diet mouse model of myocardial infarction.
Does tRF-Glu inhibition prevent cardiomyocyte pyroptosis and cardiac injury in a mouse model of myocardial infarction?
The gut microbial metabolite TMAO exacerbates post-myocardial infarction cardiac injury via the tRF-Glu–ANT1–GSDMD pathway, highlighting tRF-Glu as a potential therapeutic target to prevent cardiomyocyte pyroptosis.
Recent research has shown that the gut microbiota arrests the progression of myocardial infarction (MI) by modulating immune inflammation, oxidative stress, and metabolism. However, the mechanism by which gut-derived trimethylamine N-oxide (TMAO) promotes cardiomyocyte pyroptosis following MI remains unclear. We found that a high-choline diet exacerbated cardiac injury in mice by disrupting the intestinal barrier. Under high-choline conditions, the expression levels of tRF-1:31-Glu-TTC-2 (tRF-Glu) derived from tRF and tiRNAs (tsRNAs) were elevated, serving as a key target for intervention in cardiomyocyte pyroptosis. Loss of tRF-Glu significantly ameliorated TMAO-induced deterioration of myocardial fibrosis and cardiac function. Mechanistically, tRF-Glu directly binds to the mitochondrial inner membrane protein ANT1 and stabilizes its expression by inhibiting ubiquitination. Cardiomyocyte knockdown of ANT1 significantly blocked the generation of TMAO-induced cardiomyocyte mitochondrial reactive oxygen species, restored cardiomyocyte membrane potential, and reduced mitochondrial DNA (mtDNA) leakage. Our findings indicate that tRF-Glu inhibits the ubiquitination of ANT1 under the induction of TMAO, which in turn activates gasdermin D (GSDMD) and mtDNA release, accelerating cardiac remodeling. In conclusion, our study provides new insights into the role of the gut microbial metabolite-driven tRF-Glu–ANT1–GSDMD pathway in blocking cardiomyocyte pyroptosis and cardiac injury.
Wang et al. (Tue,) conducted a other in Myocardial infarction. High-choline diet; tRF-Glu antagomir vs. Standard rodent chow diet; negative control (NC) antagomir was evaluated on Cardiac injury assessed by myocardial fibrosis and left ventricular function (ejection fraction), cardiomyocyte pyroptosis. Suppression of tRF-Glu with antagomir significantly ameliorated TMAO-induced myocardial fibrosis and improved cardiac function in a high-choline diet mouse model of myocardial infarction.