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

Acta Pharmacologica Sinica volume 46, pages 1236–1249 (2025)Cite this article

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.

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Fig. 1: Increased expression of eIF4A1 in I/R mouse hearts and H2O2- or H/R-treated cardiomyocytes.
Fig. 2: Effects of eIF4A1 on cardiomyocyte apoptosis.
Fig. 3: eIF4A1 deficiency improved cardiac function and rescued cell apoptosis following I/R injury.
Fig. 4: eIF4A1 binding to Tagln inhibited its ubiquitination.
Fig. 5: Effects of Tagln on cardiomyocyte apoptosis.
Fig. 6: EIF4A1 mediated cardiomyocyte apoptosis through Tagln/p53 pathway.
Fig. 7: Pro-apoptotic effects of eIF4A1 in AC16 cells.
Fig. 8

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Acknowledgements

This work was supported by National Natural Science Foundation of China (No. 82470285, 82070283, 82170393), National Key Research and Development Program of Ministry of Science and Technology (2023YFA1800902), and Haiyan Funding of Harbin Medical University Cancer Hospital (JJYQ2024-08).

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Author notes

  1. These authors contributed equally: Dan-yang Li, Xiao-xi Hu.

Authors and 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

    Dan-yang Li, Xiao-xi Hu, Zhong-rui Tian, Jiang-qi Liu, Ying Yue, Wei Yuan, Bo Meng, Jia-liang Li, Yang Zhang, Zhen-wei Pan, Yu-ting Zhuang & Yan-jie Lu

  2. Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, 150086, China

    Dan-yang Li & Yan-jie Lu

  3. Scientific Research Center, Harbin Medical University Cancer Hospital, Harbin, 150081, China

    Qi-wen Ning & Yu-ting Zhuang

  4. Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, 150081, China

    Qi-wen Ning & Yu-ting Zhuang

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Contributions

YJL, ZWP, YTZ, and DYL conceived and designed the research plan. DYL, XXH, ZRT, QWN, JQL, YY, WY, and BM contributed to data acquisition, data analysis, and data interpretation. JLL and YZ contributed to development or design of methodology. DYL, XXH, YTZ, YZ, YJL, and ZWP verified the data in the study. DYL, YTZ, YJL, and ZWP drafted the manuscript and all authors read and approved the final version of the manuscript.

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Correspondence to Zhen-wei Pan, Yu-ting Zhuang or Yan-jie Lu.

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Li, Dy., Hu, Xx., Tian, Zr. et al. eIF4A1 exacerbates myocardial ischemia-reperfusion injury in mice by promoting nuclear translocation of transgelin/p53. Acta Pharmacol Sin 46, 1236–1249 (2025). https://doi.org/10.1038/s41401-024-01467-6

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