Melatonin reduces PERK-eIF2α-ATF4-mediated endoplasmic reticulum stress during myocardial ischemia–reperfusion injury: role of RISK and SAFE pathways interaction
Autor: | Wensheng Chen, Zhenhua Liu, Jian Yang, Dinghua Yi, Liming Yu, Jincheng Liu, Guolong Zhao, Buying Li, Weixun Duan, Zhenxiao Jin, Siwang Wang, Yang Yang, Shiqiang Yu, Meng Zhang |
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Rok vydání: | 2016 |
Předmět: |
Male
0301 basic medicine Cancer Research medicine.medical_specialty Eukaryotic Initiation Factor-2 Clinical Biochemistry Myocardial Ischemia Pharmaceutical Science Myocardial Reperfusion Injury medicine.disease_cause Melatonin Glycogen Synthase Kinase 3 Phosphatidylinositol 3-Kinases eIF-2 Kinase 03 medical and health sciences chemistry.chemical_compound Internal medicine medicine Animals Humans LY294002 Phosphorylation Protein kinase B PI3K/AKT/mTOR pathway Pharmacology business.industry Myocardium Biochemistry (medical) Cell Biology Endoplasmic Reticulum Stress medicine.disease Activating Transcription Factor 4 Protein kinase R Mice Inbred C57BL Oxidative Stress 030104 developmental biology Endocrinology chemistry Unfolded protein response business Reperfusion injury Oxidative stress Signal Transduction medicine.drug |
Zdroj: | Apoptosis. 21:809-824 |
ISSN: | 1573-675X 1360-8185 |
Popis: | 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. |
Databáze: | OpenAIRE |
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