title: Melatonin reduces PERK-eIF2α-ATF4-mediated endoplasmic reticulum stress during myocardial ischemia-reperfusion injury: role of RISK and SAFE pathways interaction.
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.
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, 710032, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, 710032, China.
authors.forename: Buying
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Natural Medicine, School of Pharmacy, Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, 710032, China.
authors.forename: Zhenxiao
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, 710032, China.
authors.forename: Weixun
authors.initials: W
authors.lastname: Duan
authors.affiliation: Department of Cardiovascular Surgery, General Hospital, Ningxia Medical University, 804 Shengli South Street, Yinchuan, 750004, China.
authors.forename: Guolong
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Biomedical Engineering, Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, 710032, China.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, 710032, China.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Natural Medicine, School of Pharmacy, Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, China.
authors.forename: Siwang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, 710032, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, 710032, China.
authors.forename: Dinghua
authors.initials: D
authors.lastname: Yi
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, 710032, China. liujinchenghos@126.com.
authors.forename: Jincheng
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, 710032, China. shiqiangyu210@126.com.
authors.forename: Shiqiang
authors.initials: S
authors.lastname: Yu
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D059865:Endoplasmic Reticulum Stress; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008550:Melatonin / Q000008:administration & dosage*; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D051701:Activating Transcription Factor 4; D015852:Eukaryotic Initiation Factor-2; D038362:Glycogen Synthase Kinase 3; D008550:Melatonin; D019869:Phosphatidylinositol 3-Kinases; D019892:eIF-2 Kinase
keywords: Endoplasmic reticulum stress; Melatonin; Myocardial ischemia–reperfusion injury; Reperfusion injury salvage kinase pathway; Survivor activating factor enhancement pathway