期刊
JOURNAL OF PINEAL RESEARCH
卷 59, 期 4, 页码 420-433出版社
WILEY
DOI: 10.1111/jpi.12272
关键词
melatonin; melatonin receptor; myocardial ischemia-reperfusion; Notch1 signaling; oxidative stress
资金
- International Scientific and Technological Cooperation and Exchange Project of Shaanxi Province [2015KW-047]
- Social Development Project of Shaanxi Province [2015SF104, 2012K15-02-01]
- National Natural Science Foundation of China [81470415, 81270170, 81200151, 81470411]
- National 12th Five Year Plan for Science and Technology [2011BAI11B20]
- Science and Technology Co-ordinating Innovative Engineering Project of Shaanxi Province [2013KTCL03-01]
- Natural Science Foundation of Shannxi Province [2014JM4106]
- Subject Boosting Project of Xijing Hospital [XJZT14203, XJGX12C11, XJGX13LC15]
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 (10mg/kg/day) for 4wk 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 (100mol/L) attenuated simulated ischemia-reperfusion (SIR)-induced myocardial apoptosis and oxidative damage. Both invivo and invitro 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.
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