eIF4A1 exacerbates myocardial ischemia-reperfusion injury in mice by promoting nuclear translocation of transgelin/p53.

Abstract

Eukaryotic translation initiation factor 4A1 (eIF4A1) is an ATP-dependent RNA helicase that participates in a variety of biological and pathological processes such as cell proliferation and apoptosis, and cancer. In this study we investigated the role of eIF4A1 in ischemic heart disease. The myocardial ischemia/reperfusion (I/R) model was established in mice by ligation of the left anterior descending artery for 45 min with the subsequent reperfusion for 24 h; cultured neonatal mouse ventricular cardiomyocytes (NMVCs) treated with H₂O₂ (200 μM) or H/R (12 h hypoxia and 12 h reoxygenation) were used for in vitro study. We showed that the expression levels of eIF4A1 were significantly increased in I/R-treated myocardium and in H₂O₂- or H/R-treated NMVCs. In NMVCs, eIF4A1 overexpression drastically enhanced LDH level, caspase 3 activity, and cell apoptosis. eIF4A1 overexpression also significantly reduced anti-apoptotic protein Bcl2 and elevated pro-apoptotic protein Bax expression, whereas eIF4A1 deficiency produced the opposite responses. Importantly, cardiomyocyte-specific eIF4A1 knockout attenuated cardiomyocyte apoptosis, reduced infarct area, and improved cardiac function in myocardial I/R mice. We demonstrated that eIF4A1 directly bound to transgelin (Tagln) to prevent its ubiquitination degradation and subsequent up-regulation of p53, and then promoted nuclear translocation of Tagln and p53. Nuclear localization of Tagln and p53 was increased in H₂O₂-treated NMVCs. Silencing Tagln reversed the pro-apoptotic effects of eIF4A1. Noticeably, eIF4A1 exerted the similar effects in AC16 human cardiomyocytes. In conclusion, eIF4A1 is a detrimental factor in myocardial I/R injury via promoting expression and nuclear translocation of Tagln and p53 and might be a potential target for myocardial I/R injury. This study highlights a novel biological role of eIF4A1 by interacting with non-translational-related factor Tagln in myocardial I/R injury.