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

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 (33mM) 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 up‐regulating Notch1, N1ICD, Hes1 and p‐Akt expressions, increasing Trx activity and down‐regulated 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...

Source: Journal of Pineal Research - September 30, 2016 Category: Research Authors: Liming Yu, Chongxi Fan, Zhi Li, Jian Zhang, Xiaodong Xue, Yinli Xu, Guolong Zhao, Yang Yang, Huishan Wang Tags: Original Article Source Type: research