SIRT1 suppresses cardiomyocyte apoptosis in diabetic cardiomyopathy: An insight into endoplasmic reticulum stress response mechanism
SIRT1 suppresses cardiomyocyte apoptosis in diabetic cardiomyopathy: An insight into endoplasmic reticulum stress response mechanism
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DOI：
10.1016/j.ijcard.2015.04.245
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发表时间：
2015-07-15
影响因子：
3.5
通讯作者：
Xu, Yawei
中科院分区：
文献类型：
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作者：
Guo, Rong;Liu, Weijing;Xu, Yawei
背景：内质网（ER）应激依赖性凋亡已被证明发生在糖尿病患者的心脏中，尽管确切的机制尚不清楚。SIRT1 （SIRT1）是一种烟酰胺腺嘌呤二核苷酸NAD（+）依赖性去乙酰化酶，已知在糖尿病相关并发症和内质网应激中发挥作用。因此，我们研究了SIRT1 （SIRT1）与内质网应激诱导的H9C2心肌细胞凋亡的关系。方法：采用高脂饲料单次腹腔注射链脲佐菌素（STZ, 50 mg/kg）建立糖尿病大鼠模型。为了进行体外分析，我们培养了大鼠源性H9C2心肌细胞。采用多普勒法检测心功能，免疫组织化学和免疫印迹法检测SIRT1和内质网应激相关蛋白的表达。将培养的细胞暴露于晚期糖基化终产物（AGEs） （400 μ g/mL）中诱导内质网应激和凋亡。流式细胞术检测细胞凋亡。结果：在体内，未经任何处理的糖尿病大鼠心肌细胞内质网应激增强。SIRT1激活剂白藜芦醇可以显著恢复心功能，减少心肌细胞凋亡，改善内质网应激。在体外，我们发现当SIRT1表达被短干扰RNA （siRNA）下调时，AGE刺激后细胞凋亡和内质网应激增加（p < 0.05）。然而，白藜芦醇（10 μ M）恢复心肌细胞SIRT1水平，并显著减少内质网应激介导的细胞凋亡。结论：SIRT1可能通过PERK/eIF2 α、ATF6/CHOP和IRE1 α / jnk介导的途径减弱内质网应激诱导的心肌细胞凋亡。这项研究可能为糖尿病性心肌病的治疗提供新的潜在机制和策略。2015爱思唯尔爱尔兰有限公司版权所有。
Background: Endoplasmic reticulum (ER) stress-dependent apoptosis had been shown to occur in the hearts of people with diabetes, although the exact mechanisms are unclear. Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide NAD(+)-dependent deacetylase, is known to play a role in diabetes-related complications as well as ER-stress. Therefore, we investigated the relationship between Sirtuin 1 (SIRT1) and ER stress-induced apoptosis in H9C2 cardiomyocyte.Methods: Diabetic rats were established by a single intraperitoneal injection of streptozotocin (STZ; 50 mg/kg) with high-fat diet. For in vitro analysis, rat derived H9C2 cardiomyocytes were cultured. Cardiac function was assessed by Doppler, and SIRT1 as well as ER stress related protein expressions were measured by immunohistochemistry and western blotting. Cultured cells were exposed to advanced glycation end products (AGEs) (400 mu g/mL) for inducing ER stress and apoptosis. Cell apoptosis were detected by flow cytometry.Results: In vivo, ER stress was enhanced in the cardiomyocytes of diabetic rats without any treatments. A SIRT1 activator, resveratrol, could significantly restore cardiac function, reduce cardiomyocyte apoptosis, and ameliorate ER stress. In vitro, we showed that apoptosis and ER stress increased after AGE stimulation when SIRT1 expression was downregulated by short interfering RNA (siRNA) (p < 0.05). However, resveratrol (10 mu M) restored SIRT1 levels in cardiomyocytes and markedly reduced ER stress-mediated apoptosis.Conclusion: SIRT1 may attenuate ER stress-induced cardiomyocyte apoptosis via PERK/eIF2 alpha, ATF6/CHOP, and IRE1 alpha/JNK-mediated pathways. This study may provide insights into a novel underlying mechanism and a strategy for treating diabetic cardiomyopathy. (C) 2015 Elsevier Ireland Ltd. All rights reserved.