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

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

  • Acta Pharmacol Sin. 2025 Jan 24. doi: 10.1038/s41401-024-01467-6.
Dan-Yang Li # 1 2,  Xiao-Xi Hu # 1,  Zhong-Rui Tian 1,  Qi-Wen Ning 3 4,  Jiang-Qi Liu 1,  Ying Yue 1,  Wei Yuan 1,  Bo Meng 1,  Jia-Liang Li 1,  Yang Zhang 1,  Zhen-Wei Pan 5,  Yu-Ting Zhuang 6 7 8,  Yan-Jie Lu 9 10
Affiliations

Affiliations

  • 1 Department of Pharmacology, National Key Laboratory of Frigid Zone Cardiovascular Diseases, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150086, China.
  • 2 Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, 150086, China.
  • 3 Scientific Research Center, Harbin Medical University Cancer Hospital, Harbin, 150081, China.
  • 4 Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, 150081, China.
  • 5 Department of Pharmacology, National Key Laboratory of Frigid Zone Cardiovascular Diseases, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150086, China. panzw@ems.hrbmu.edu.cn.
  • 6 Department of Pharmacology, National Key Laboratory of Frigid Zone Cardiovascular Diseases, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150086, China. zhuangyuting@hrbmu.edu.cn.
  • 7 Scientific Research Center, Harbin Medical University Cancer Hospital, Harbin, 150081, China. zhuangyuting@hrbmu.edu.cn.
  • 8 Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, 150081, China. zhuangyuting@hrbmu.edu.cn.
  • 9 Department of Pharmacology, National Key Laboratory of Frigid Zone Cardiovascular Diseases, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150086, China. yjlu@hrbmu.edu.cn.
  • 10 Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, 150086, China. yjlu@hrbmu.edu.cn.
  • # Contributed equally.
PMID: 39856433 DOI: 10.1038/s41401-024-01467-6
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.

Keywords

Tagln; apoptosis; eIF4A1; myocardial I/R injury; p53; ubiquitination.

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