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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\u2010reperfusion (<jats:styled-content style=\"fixed-case\">MI<\/jats:styled-content>\/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 <jats:styled-content style=\"fixed-case\">MI<\/jats:styled-content>\/R surgery and high\u2010glucose (<jats:styled-content style=\"fixed-case\">HG<\/jats:styled-content>, 500\u00a0g\/L) infusion (4\u00a0mL\/kg\/h) to induce temporary hyperglycemia. Rats were treated with or without melatonin (10\u00a0mg\/kg\/d) during the operation. Furthermore, <jats:styled-content style=\"fixed-case\">HG<\/jats:styled-content> (33\u00a0mmol\/L)\u2010incubated H9c2 cardiomyoblasts were treated in the presence or absence of luzindole (a competitive melatonin receptor antagonist), <jats:styled-content style=\"fixed-case\">DAPT<\/jats:styled-content> (a \u03b3\u2010secretase inhibitor), <jats:styled-content style=\"fixed-case\">LY<\/jats:styled-content>294002 (a <jats:styled-content style=\"fixed-case\">PI<\/jats:styled-content>3\u2010kinase\/Akt inhibitor), or thioredoxin\u2010interacting protein (Txnip) adenoviral vectors. We found that acute hyperglycemia aggravated <jats:styled-content style=\"fixed-case\">MI<\/jats:styled-content>\/R injury by suppressing Notch1\/Hes1\/Akt signaling and intracellular Trx activity. Melatonin treatment effectively ameliorated <jats:styled-content style=\"fixed-case\">MI<\/jats:styled-content>\/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, N1<jats:styled-content style=\"fixed-case\">ICD<\/jats:styled-content>, Hes1, and p\u2010Akt expressions, increasing Trx activity, and downregulating Txnip expression. However, these effects were blunted by luzindole, <jats:styled-content style=\"fixed-case\">DAPT<\/jats:styled-content>, or <jats:styled-content style=\"fixed-case\">LY<\/jats:styled-content>294002. Additionally, Txnip overexpression not only decreased Trx activity, but also attenuated the cytoprotective effect of melatonin. We conclude that impaired Notch1 signaling aggravates <jats:styled-content style=\"fixed-case\">MI<\/jats:styled-content>\/R injury in acute hyperglycemic state. Melatonin rescues Trx system by reducing Txnip expression via Notch1\/Hes1\/Akt signaling in a membrane receptor\u2010dependent manner. Its role as a prophylactic\/therapeutic drug deserves further clinical study.<\/jats:p>","DOI":"10.1111\/jpi.12375","type":"journal-article","created":{"date-parts":[[2016,10,18]],"date-time":"2016-10-18T06:10:12Z","timestamp":1476771012000},"source":"Crossref","is-referenced-by-count":58,"title":["Melatonin rescues cardiac thioredoxin system during ischemia\u2010reperfusion injury in acute hyperglycemic state by restoring <scp>N<\/scp>otch1\/<scp>H<\/scp>es1\/<scp>A<\/scp>kt signaling in a membrane receptor\u2010dependent manner"],"prefix":"10.1111","volume":"62","author":[{"given":"Liming","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Surgery General Hospital of Shenyang Military Area Command  Shenyang Liaoning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chongxi","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery Tangdu Hospital The Fourth Military Medical University  Xi'an 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