title: Membrane receptor-dependent Notch1/Hes1 activation by melatonin protects against myocardial ischemia-reperfusion injury: in vivo and in vitro studies.
abstract: Melatonin confers profound protective effect against myocardial ischemia-reperfusion injury (MI/RI). Activation of Notch1/Hairy and enhancer of split 1 (Hes1) signaling also ameliorates MI/RI. We hypothesize that melatonin attenuates MI/RI-induced oxidative damage by activating Notch1/Hes1 signaling pathway with phosphatase and tensin homolog deleted on chromosome 10 (Pten)/Akt acting as the downstream signaling pathway in a melatonin membrane receptor-dependent manner. Male Sprague Dawley rats were treated with melatonin (10 mg/kg/day) for 4 wk and then subjected to MI/R surgery. Melatonin significantly improved cardiac function and decreased myocardial apoptosis and oxidative damage. Furthermore, in cultured H9C2 cardiomyocytes, melatonin (100 μmol/L) attenuated simulated ischemia-reperfusion (SIR)-induced myocardial apoptosis and oxidative damage. Both in vivo and in vitro study demonstrated that melatonin treatment increased Notch1, Notch1 intracellular domain (NICD), Hes1, Bcl-2 expressions, and p-Akt/Akt ratio and decreased Pten, Bax, and caspase-3 expressions. However, these protective effects conferred by melatonin were blocked by DAPT (the specific inhibitor of Notch1 signaling), luzindole (the antagonist of melatonin membrane receptors), Notch1 siRNA, or Hes1 siRNA administration. In summary, our study demonstrates that melatonin treatment protects against MI/RI by modulating Notch1/Hes1 signaling in a receptor-dependent manner and Pten/Akt signaling pathways are key downstream mediators.
authors: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors: Liming
authors: L
authors: Yu
authors: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors: Hongliang
authors: H
authors: Liang
authors: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors: Zhihong
authors: Z
authors: Lu
authors: Department of Cardiovascular Surgery, General Hospital, Ningxia Medical University, Yinchuan, China.
authors: Guolong
authors: G
authors: Zhao
authors: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors: Mengen
authors: M
authors: Zhai
authors: Department of Biomedical Engineering, The Fourth Military Medical University, Xi'an, China.
authors: Yang
authors: Y
authors: Yang
authors: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors: Jian
authors: J
authors: Yang
authors: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors: Dinghua
authors: D
authors: Yi
authors: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors: Wensheng
authors: W
authors: Chen
authors: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors: Xiaowu
authors: X
authors: Wang
authors: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors: Weixun
authors: W
authors: Duan
authors: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors: Zhenxiao
authors: Z
authors: Jin
authors: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors: Shiqiang
authors: S
authors: Yu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008550:Melatonin / Q000494:pharmacology* / Q000627:therapeutic use*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D044094:Receptors, Melatonin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D053148:Caspase 3; D018398:Homeodomain Proteins; D008550:Melatonin; D019253:Proto-Oncogene Proteins c-bcl-2; D051881:Receptor, Notch1; D044094:Receptors, Melatonin; D000072056:Transcription Factor HES-1; C489735:Hes1 protein, rat
keywords: Notch1 signaling; melatonin; melatonin receptor; myocardial ischemia-reperfusion; oxidative stress