Hydrogen sulfide restores sevoflurane postconditioning mediated cardioprotection in diabetic rats: Role of SIRT1/Nrf2 signaling-modulated mitochondrial dysfunction and oxidative stress
Hydrogen sulfide restores sevoflurane postconditioning mediated cardioprotection in diabetic rats: Role of SIRT1/Nrf2 signaling-modulated mitochondrial dysfunction and oxidative stress
复制标题
硫化氢恢复糖尿病大鼠七氟烷后处理介导的心脏保护作用：SIRT1/Nrf2 信号调节线粒体功能障碍和氧化应激的作用
DOI：
10.1002/jcp.30214
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发表时间：
2020-12-15
影响因子：
5.6
通讯作者：
Yu, Peng
中科院分区：
文献类型：
--
作者：
Zhang, Jing;Cai, Xia;Yu, Peng
糖尿病心脏易受心肌缺血/再灌注损伤（IRI）的影响，但对七氟烷后处理（SPC）不敏感，从而激活可提供心脏保护的过氧化物酶。已有研究表明，硫化氢（H2S）可通过增加沉默信息调节因子2相关酶1（SIRT 1）的表达抑制糖尿病大鼠的氧化应激，但SPC的心脏保护作用能否在其后恢复尚不清楚。对糖尿病大鼠进行IRI（缺血30 min，再灌注120 min）。再灌注开始后，给予七氟烷后处理15分钟。实验前5天用GYY 4137（H2S供体）处理糖尿病大鼠。检测再灌注后心肌梗死面积、线粒体结构和功能、ATP含量、复合物I-IV活性、氧化应激标志物、SIRT 1、核因子E2相关因子2（Nrf 2）、血红素加氧酶-1（HO-1）、NADPH氧化酶-2（Nox-2）蛋白表达，并于再灌注24 h超声心动图评价心功能。在糖尿病大鼠受损心肌中，H2S激活SIRT 1后，SPC显著上调Nrf 2及其下游介质HO-1的表达，从而降低Nox-2的表达。此外，H2S显著增加细胞质和细胞核SIRT 1，SPC进一步增强。此外，H2S与SPC的结合减少了活性氧的产生，增加了ATP的含量，并保持了线粒体酶的活性。心肌梗死范围缩小，心肌损伤减轻，心功能改善。综上所述，我们的研究证明，H2S可以通过增强和促进SIRT 1/Nrf 2信号通路介导的线粒体功能障碍和氧化应激来恢复SPC诱导的糖尿病大鼠心脏保护作用。
Diabetic hearts are vulnerable to myocardial ischemia/reperfusion injury (IRI), but are insensitive to sevoflurane postconditioning (SPC), activating peroxiredoxins that confer cardioprotection. Previous studies have demonstrated that hydrogen sulfide (H2S) can suppress oxidative stress of diabetic rats through increasing the expression of silent information regulator factor 2-related enzyme 1 (SIRT1), but whether cardioprotection by SPC can be restored afterward remains unclear. Diabetic rat was subjected to IRI (30 min of ischemia followed by 120 min reperfusion). Postconditioning treatment with sevoflurane was administered for 15 min upon the onset of reperfusion. The diabetic rats were treated with GYY4137 (H2S donor) 5 days before the experiment. Myocardial infarct size, mitochondrial structure and function, ATP content, activities of complex I-IV, marker of oxidative stress, SIRT1, nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NADPH Oxidase-2 (Nox-2) protein expression were detected after reperfusion, and cardiac function was evaluated by echocardiography at 24 h after reperfusion. After H2S activated SIRT1 in the impaired myocardium of diabetic rats, SPC significantly upregulated the expression of Nrf2 and its downstream mediator HO-1, thus reduced the expression of Nox-2. In addition, H2S remarkably increased cytoplasmic and nuclear SIRT1 which was further enhanced by SPC. Furthermore, H2S combined with SPC reduced the production of reactive oxygen species, increased the content of ATP, and maintained mitochondrial enzyme activity. Finally, myocardial infarct size and myocardium damage were decreased, and cardiac function was improved. Taken together, our study proved that H2S could restore SPC-induced cardioprotection in diabetic rats by enhancing and promoting SIRT1/Nrf2 signaling pathway mediated mitochondrial dysfunction and oxidative stress.