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
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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