title: Melatonin rescues cardiac thioredoxin system during ischemia-reperfusion injury in acute hyperglycemic state by restoring Notch1/Hes1/Akt signaling in a membrane receptor-dependent manner.
abstract: Stress hyperglycemia is commonly observed in patients suffering from ischemic heart disease. It not only worsens cardiovascular prognosis but also attenuates the efficacies of various cardioprotective agents. This study aimed to investigate the protective effect of melatonin against myocardial ischemia-reperfusion (MI/R) injury in acute hyperglycemic state with a focus on Notch1/Hes1/Akt signaling and intracellular thioredoxin (Trx) system. Sprague Dawley rats were subjected to MI/R surgery and high-glucose (HG, 500 g/L) infusion (4 mL/kg/h) to induce temporary hyperglycemia. Rats were treated with or without melatonin (10 mg/kg/d) during the operation. Furthermore, HG (33 mmol/L)-incubated H9c2 cardiomyoblasts were treated in the presence or absence of luzindole (a competitive melatonin receptor antagonist), DAPT (a γ-secretase inhibitor), LY294002 (a PI3-kinase/Akt inhibitor), or thioredoxin-interacting protein (Txnip) adenoviral vectors. We found that acute hyperglycemia aggravated MI/R injury by suppressing Notch1/Hes1/Akt signaling and intracellular Trx activity. Melatonin treatment effectively ameliorated MI/R injury by reducing infarct size, myocardial apoptosis, and oxidative stress. Moreover, melatonin also markedly enhanced Notch1/Hes1/Akt signaling and rescued intracellular Trx system by upregulating Notch1, N1ICD, Hes1, and p-Akt expressions, increasing Trx activity, and downregulating Txnip expression. However, these effects were blunted by luzindole, DAPT, or LY294002. Additionally, Txnip overexpression not only decreased Trx activity, but also attenuated the cytoprotective effect of melatonin. We conclude that impaired Notch1 signaling aggravates MI/R injury in acute hyperglycemic state. Melatonin rescues Trx system by reducing Txnip expression via Notch1/Hes1/Akt signaling in a membrane receptor-dependent manner. Its role as a prophylactic/therapeutic drug deserves further clinical study.
authors.affiliation: Department of Cardiovascular Surgery, General Hospital of Shenyang Military Area Command, Shenyang, Liaoning, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Chongxi
authors.initials: C
authors.lastname: Fan
authors.affiliation: Department of Cardiovascular Surgery, General Hospital of Shenyang Military Area Command, Shenyang, Liaoning, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Cardiovascular Surgery, General Hospital of Shenyang Military Area Command, Shenyang, Liaoning, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cardiovascular Surgery, General Hospital of Shenyang Military Area Command, Shenyang, Liaoning, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Xue
authors.affiliation: Department of Cardiovascular Surgery, General Hospital of Shenyang Military Area Command, Shenyang, Liaoning, China.
authors.forename: Yinli
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Cardiovascular Surgery, Northwest Women's and Children's Hospital, Xi'an, Shaanxi, China.
authors.forename: Guolong
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Biomedical Engineering, The Fourth Military Medical University, Xi'an, China.|Department of Thoracic and Cardiovascular Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Cardiovascular Surgery, General Hospital of Shenyang Military Area Command, Shenyang, Liaoning, China.
authors.forename: Huishan
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D006943:Hyperglycemia / Q000150:complications*; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000517:prevention & control*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051881:Receptor, Notch1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013879:Thioredoxins / Q000378:metabolism*; D000072056:Transcription Factor HES-1 / Q000378:metabolism
chemical_list: C489735:Hes1 protein, rat; C497763:Notch1 protein, rat; D051881:Receptor, Notch1; D000072056:Transcription Factor HES-1; D013879:Thioredoxins; D051057:Proto-Oncogene Proteins c-akt; D008550:Melatonin
keywords: Notch1; hyperglycemia; melatonin; myocardial ischemia-reperfusion injury; thioredoxin; thioredoxin-interacting protein