2025 Volume 66 Issue 3 Pages 475-484
Myocardial infarction (MI) is one of the leading causes of mortality in the world. Ischemia-reperfusion injury (IR) means that reperfusion therapy after MI aggravates its structural destruction, causes cell death, and leads to further damage to cardiac function. Remimazolam shows significant anti-myocardial I/R injury activity by inhibiting inflammation, alleviating MI, and enhancing cardiac function. However, the molecular mechanism is not clear. RNA N4-acetylcytidine (ac4C) modification, which is mediated by the ac4C writer N-acetyltransferase 10 (Nat10), is involved in MI. In this study, we explored the role of ac4C acetylation in the reduction of myocardial damage by treatment with remimazolam. The effect of remimazolam on myocardial I/R injury (MIRI) was examined using an MIRI mouse model. The H9C2 cells received hypoxia/reoxygenation (H/R) to simulate the condition of I/R in vivo. Pyroptosis in H9C2 cells was assessed by measuring the release of lactic dehydrogenase, and NLRP3-dependent release of inflammatory factors. The underlying mechanism was investigated by quantitative real-time PCR, Western blot, and RNA immunoprecipitation (RIP). The results suggested that remimazolam alleviated myocardial damage and inhibited NLRP3-dependent pyroptosis induced by H/R injury. Nat10-mediated ac4C acetylation levels were inhibited by treatment with remimazolam, which was reversed by Nat10 overexpression in the H/R cell model. We then found that Nat10 facilitated the ac4C acetylation of Nek7 and promoted the pyroptosis of cardiomyocytes through Nek7. In conclusion, we demonstrate that remimazolam ameliorates MI by suppressing cardiomyocyte pyroptosis via inhibiting the ac4C acetylation of Nek7. The results of this study suggest a therapeutic value for remimazolam and may provide a new potential therapeutic target for MI.
