Y4 RNA fragment mitigates myocardial ischemia-reperfusion injury in heart transplantation through SNRNP200-mediated enhancement of IL-10 pre-mRNA splicing.

Abstract

Myocardial ischemia-reperfusion injury (MIRI) inevitably occurs during heart transplantation, highlighting the imperative for effective therapeutic interventions. A Y4 RNA fragment (YF1) was applied to treat a syngeneic mouse model of heart transplantation, with heart subjected to cold ischemia-reperfusion (CIR). Cardiomyocytes and macrophages were treated with YF1, and a cellular cold hypoxia-reoxygenation (CHR) model was established. We found that YF1 alleviated CIR-induced inflammatory macrophage infiltration and cardiomyocytes injury in the graft heart. YF1 had no direct effects on cardiomyocytes in vitro, while YF1 inhibited macrophage polarization to the pro-inflammatory phenotype with increased expression of anti-inflammatory factors. Moreover, YF1 attenuated CHR-induced cardiomyocyte injury by regulating the IL-10 expression in macrophages. Mechanistically, YF1 increased the mRNA expression ratio of IL-10/pre IL-10 by binding to SNRNP200, a spliceosome-specific protein for pre-mRNA splicing, with reduced SNRNP200 ubiquitination. And it was reversed by Brr2-IN-3, a specific SNRNP200 inhibitor. Collectively, we hold that YF1 might alleviate MIRI in heart transplantation via binding to SNRNP200 and regulating its ubiquitination to enhance IL-10 pre-mRNA splicing. These findings further clarify the effects and mechanism of YF1 on MIRI and suggest a potential cardioprotective therapy in heart transplantation.