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Melatonin reduces PERK-eIF2α-ATF4-mediated endoplasmic reticulum stress during myocardial ischemia–reperfusion injury: role of RISK and SAFE pathways interaction

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Abstract

Recently, we demonstrated that melatonin reduced protein kinase RNA (PKR)-like ER kinase (PERK)-eukaryotic initiation factor 2 alpha (eIF2α)-activating transcription factor-4 (ATF4)-mediated myocardial endoplasmic reticulum (ER) stress and apoptosis during myocardial ischemia–reperfusion (MI/R) injury. However, the underlying mechanisms are still not clear. Myocardial reperfusion injury salvage kinase (RISK) pathway as well as survivor activating factor enhancement (SAFE) pathway are two pivotal intrinsic pro-survival signaling cascades. In this study, we performed in vivo and in vitro experiment to investigate the ameliorative effect of melatonin on ER stress with a focus on RISK and SAFE pathways interaction. Male C57Bl/6 mice received melatonin (300 μg/25 g/day, 3 days before MI/R surgery; 300 μg/25 g, 25 min before the onset of ischemia) pre-treatment with or without the administration of LY294002 (a PI3K/Akt inhibitor), U0126 (an ERK1/2 inhibitor) or AG490 (a STAT3 pathway inhibitor). H9c2 cells were pre-treated with melatonin (100 μM, 8 h) in the presence or absence of LY294002, U0126 or AG490. Compared with the I/R-injured group, melatonin effectively reduced myocardial apoptosis, oxidative stress and improved cardiac function. In addition, melatonin pre-treatment also increased the phosphorylation of Akt, GSK-3β, ERK1/2 and STAT3 and reduced PERK-eIF2α-ATF4-mediated ER stress. However, these effects were blocked by LY294002, U0126 or AG490. Additionally, either LY294002 or U0126 treatment could inhibit STAT3 phosphorylation, whereas AG490 administration also reduced both Akt and ERK1/2 phosphorylation, indicating an interplay exists between RISK and SAFE pathways in melatonin’s cardioprotective effect. In summary, our study demonstrates that RISK and SAFE pathways mediate the cardioprotective effect of melatonin against MI/R injury. Melatonin pre-treatment attenuates PERK-eIF2α-ATF4-mediated ER stress and apoptosis during MI/R injury via RISK and SAFE pathways interaction.

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Acknowledgments

This work was supported by Grants from the National Natural Science Foundation of China (81470415, 81270170, 81200151, 81470411, 81570330, 81570231, 81570230, 81570232), International scientific and technological cooperation and exchange project of Shaanxi Province (2015KW-047), the Science and technology co-ordinating innovative engineering project of Shaanxi Province (2013KTCL03-01), the Subject Boosting Project of Xijing Hospital (XJZT14203, XJGX12C11, XJGX13LC15).

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    1. Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi’an, 710032, China

      Liming Yu, Buying Li, Zhenxiao Jin, Weixun Duan, Zhenhua Liu, Wensheng Chen, Jian Yang, Dinghua Yi, Jincheng Liu & Shiqiang Yu

    2. Department of Natural Medicine, School of Pharmacy, Fourth Military Medical University, 169 Changle West Road, Xi’an, 710032, China

      Meng Zhang & Siwang Wang

    3. Department of Cardiovascular Surgery, General Hospital, Ningxia Medical University, 804 Shengli South Street, Yinchuan, 750004, China

      Guolong Zhao

    4. Department of Biomedical Engineering, Fourth Military Medical University, 169 Changle West Road, Xi’an, 710032, China

      Yang Yang

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    Liming Yu, Buying Li, and Meng Zhang contributed equally to this study.

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    Yu, L., Li, B., Zhang, M. et al. Melatonin reduces PERK-eIF2α-ATF4-mediated endoplasmic reticulum stress during myocardial ischemia–reperfusion injury: role of RISK and SAFE pathways interaction. Apoptosis 21, 809–824 (2016). https://doi.org/10.1007/s10495-016-1246-1

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