Membrane receptor-dependent Notch1/Hes1 activation by melatonin protects against myocardial ischemia-reperfusion injury: invivo and invitro studies
Membrane receptor-dependent Notch1/Hes1 activation by melatonin protects against myocardial ischemia-reperfusion injury: invivo and invitro studies
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褪黑激素对膜受体依赖性 Notch1/Hes1 的激活可防止心肌缺血再灌注损伤：体内和体外研究。
DOI：
10.1111/jpi.12272
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发表时间：
2015-11-01
影响因子：
10.3
通讯作者：
Yu, Shiqiang
中科院分区：
文献类型：
--
作者：
Yu, Liming;Liang, Hongliang;Yu, Shiqiang
褪黑素对心肌缺血再灌注损伤（MI/RI）具有深远的保护作用。Notch1/Hairy和分裂1信号增强子（Hes1）的激活也能改善MI/RI。我们假设褪黑激素通过激活Notch1/Hes1信号通路来减弱MI/ ri诱导的氧化损伤，Notch1/Hes1信号通路是10号染色体上缺失的磷酸酶和紧张素同源物(Pten)/Akt以褪黑激素膜受体依赖的方式作为下游信号通路。雄性Sprague Dawley大鼠给予褪黑素（10mg/kg/d）治疗4周后行心肌梗死/再灌注手术。褪黑素显著改善心功能，减少心肌细胞凋亡和氧化损伤。此外，在培养的H9C2心肌细胞中，褪黑素（100mol/L）可减轻模拟缺血再灌注（SIR）诱导的心肌凋亡和氧化损伤。体内和体外研究均表明，褪黑素处理增加了Notch1、Notch1胞内结构域（NICD）、Hes1、Bcl-2表达和p-Akt/Akt比值，降低了Pten、Bax和caspase-3的表达。然而，褪黑激素赋予的这些保护作用被DAPT （Notch1信号的特异性抑制剂）、luzindole（褪黑激素膜受体的拮抗剂）、Notch1 siRNA或Hes1 siRNA阻断。总之，我们的研究表明，褪黑激素治疗通过以受体依赖的方式调节Notch1/Hes1信号通路来预防MI/RI，而Pten/Akt信号通路是关键的下游介质。
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.