PRJNA869493
tsRNA-5008a promotes ferroptosis in cardiomyocytes that causes structural remodeling predisposed to atrial fibrillation
Aims: Atrial fibrillation (AF) is an extremely common clinical arrhythmia disease, but whether its mechanism is associated with ferroptosis remains unclear. The tRNA-derived small RNAs (tsRNAs) are a new class of functional small molecules involved in a variety of cardiovascular diseases, however, their role and mechanism in atrial remodeling in AF have not been studied. We aimed to explore whether tsRNAs mediate ferroptosis in AF progression.Methods: The AF models were constructed to detect ferroptosis-related indicators, and Ferrostatin-1 (Fer-1) was introduced to clarify the relationship between ferroptosis and AF. Atrial myocardial tissue was used for small RNA sequencing to screen potential tsRNAs. tsRNA knockout functioned on ferroptosis and AF was explored.Result: Atrial fibrosis and changes in the cellular structures and arrangement were observed in AF mice model, and these alterations were accompanied by ferroptosis occurrence, exhibited by the accumulation of Fe2+ and MDA levels and the decrease of expression of FTH1, GPX4, and SLC7A11. Blocking above ferroptosis activation with Fer-1 resulted in a significant improvement for AF. A total of 7 tsRNAs were upregulated (including tsRNA-5008a) and 2 tsRNAs were downregulated in atrial myocardial tissue in the AF group compared with sham group. We constructed a tsRNA-mRNA regulated network, which showed tsRNA-5008a targeted 16 ferroptosis-related genes. Knockdown of tsRNA-5008a significantly suppressed ferroptosis and diminished myocardial fibrosis.Conclusion: AF development accompanied by ferroptosis and abnormal of tsRNAs expression profile. Knockdown of tsRNA-5008a diminished AF through ferroptosis suppression. Our study provides a novel insight into the role of tsRNA-5008a mediated ferroptosis in AF progression and therapeutic target for AF.