Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
Department of Cardiovascular Surgery, General Hospital, Ningxia Medical University, Yinchuan, China.
J Pineal Res. 2015 Oct;59(3):376-90. doi: 10.1111/jpi.12269. Epub 2015 Sep 11.
Diabetes mellitus (DM) increases myocardial oxidative stress and endoplasmic reticulum (ER) stress. Melatonin confers cardioprotective effect by suppressing oxidative damage. However, the effect and mechanism of melatonin on myocardial ischemia-reperfusion (MI/R) injury in type 2 diabetic state are still unknown. In this study, we developed high-fat diet-fed streptozotocin (HFD-STZ) rat, a well-known type 2 diabetic model, to evaluate the effect of melatonin on MI/R injury with a focus on silent information regulator 1 (SIRT1) signaling, oxidative stress, and PERK/eIF2α/ATF4-mediated ER stress. HFD-STZ treated rats were exposed to melatonin treatment in the presence or the absence of sirtinol (a SIRT1 inhibitor) and subjected to MI/R surgery. Compared with nondiabetic animals, type 2 diabetic rats exhibited significantly decreased myocardial SIRT1 signaling, increased apoptosis, enhanced oxidative stress, and ER stress. Additionally, further reduced SIRT1 signaling, aggravated oxidative damage, and ER stress were found in diabetic animals subjected to MI/R surgery. Melatonin markedly reduced MI/R injury by improving cardiac functional recovery and decreasing myocardial apoptosis in type 2 diabetic animals. Melatonin treatment up-regulated SIRT1 expression, reduced oxidative damage, and suppressed PERK/eIF2α/ATF4 signaling. However, these effects were all attenuated by SIRT1 inhibition. Melatonin also protected high glucose/high fat cultured H9C2 cardiomyocytes against simulated ischemia-reperfusion injury-induced ER stress by activating SIRT1 signaling while SIRT1 siRNA blunted this action. Taken together, our study demonstrates that reduced cardiac SIRT1 signaling in type 2 diabetic state aggravates MI/R injury. Melatonin ameliorates reperfusion-induced oxidative stress and ER stress via activation of SIRT1 signaling, thus reducing MI/R damage and improving cardiac function.
糖尿病（DM）增加心肌氧化应激和内质网（ER）应激。褪黑素通过抑制氧化损伤发挥心脏保护作用。然而，褪黑素在 2 型糖尿病状态下对心肌缺血再灌注（MI/R）损伤的作用和机制尚不清楚。在这项研究中，我们构建了高脂肪饮食喂养链脲佐菌素（HFD-STZ）大鼠，这是一种著名的 2 型糖尿病模型，以评估褪黑素对 MI/R 损伤的影响，重点关注沉默信息调节因子 1（SIRT1）信号、氧化应激和 PERK/eIF2α/ATF4 介导的 ER 应激。用或不用 Sirtinol（SIRT1 抑制剂）处理 HFD-STZ 处理的大鼠，并进行 MI/R 手术。与非糖尿病动物相比，2 型糖尿病大鼠表现出明显降低的心肌 SIRT1 信号、增加的凋亡、增强的氧化应激和 ER 应激。此外，在经历 MI/R 手术的糖尿病动物中，发现 SIRT1 信号进一步降低，氧化损伤和 ER 应激加重。褪黑素通过改善心脏功能恢复和减少 2 型糖尿病动物的心肌凋亡，显著减轻 MI/R 损伤。褪黑素治疗可上调 SIRT1 表达，减少氧化损伤，并抑制 PERK/eIF2α/ATF4 信号。然而，这些作用都被 SIRT1 抑制所削弱。褪黑素还通过激活 SIRT1 信号来保护高葡萄糖/高脂肪培养的 H9C2 心肌细胞免受模拟缺血再灌注损伤诱导的 ER 应激，而 SIRT1 siRNA 则削弱了这一作用。总之，我们的研究表明，2 型糖尿病状态下心脏 SIRT1 信号的降低加重了 MI/R 损伤。褪黑素通过激活 SIRT1 信号改善再灌注诱导的氧化应激和 ER 应激，从而减少 MI/R 损伤并改善心脏功能。
