Xie Liping, Feng Haihua, Li Sha, Meng Guoliang, Liu Shangmin, Tang Xin, Ma Yan, Han Yi, Xiao Yujiao, Gu Yue, Shao Yongfeng, Park Chung-Min, Xian Ming, Huang Yu, Ferro Albert, Wang Rui, Moore Philip K, Wang Hong, Ji Yong
1 Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University , Nanjing, China .
2 Department of Pharmacology, School of Pharmacy, Nantong University , Nantong, China .
Antioxid Redox Signal. 2016 Feb 20;24(6):329-43. doi: 10.1089/ars.2015.6331. Epub 2015 Nov 10.
Oxidative stress is a key contributor to endothelial dysfunction and associated cardiovascular pathogenesis. Hydrogen sulfide (H2S) is an antioxidant gasotransmitter that protects endothelial cells against oxidative stress. Sirtuin3 (SIRT3), which belongs to the silent information regulator 2 (SIR2) family, is an important deacetylase under oxidative stress. H2S is able to regulate the activity of several sirtuins. The present study aims to investigate the role of SIRT3 in the antioxidant effect of H2S in endothelial cells.
Cultured EA.hy926 endothelial cells were exposed to hydrogen peroxide (H2O2) as a model of oxidative stress-induced cell injury. GYY4137, a slow-releasing H2S donor, improved cell viability, reduced oxidative stress and apoptosis, and improved mitochondrial function following H2O2 treatment. H2S reversed the stimulation of MAPK phosphorylation, downregulation of SIRT3 mRNA and reduction of the superoxide dismutase 2 and isocitrate dehydrogenase 2 expression which were induced by H2O2. H2S also increased activator protein 1 (AP-1) binding activity with SIRT3 promoter and this effect was absent in the presence of the specific AP-1 inhibitor, SR11302 or curcumin. Paraquat administration to mice induced a defected endothelium-dependent aortic vasodilatation and increased oxidative stress in both mouse aorta and small mesenteric artery, which were alleviated by GYY4137 treatment. This vasoprotective effect of H2S was absent in SIRT3 knockout mice.
The present results highlight a novel role for SIRT3 in the protective effect of H2S against oxidant damage in the endothelium both in vitro and in vivo.
H2S enhances AP-1 binding activity with the SIRT3 promoter, thereby upregulating SIRT3 expression and ultimately reducing oxidant-provoked vascular endothelial dysfunction. Antioxid. Redox Signal. 24, 329-343.
氧化应激是导致内皮功能障碍及相关心血管发病机制的关键因素。硫化氢（H₂S）是一种抗氧化性气体递质，可保护内皮细胞免受氧化应激的影响。沉默信息调节因子3（SIRT3）属于沉默信息调节因子2（SIR2）家族，是氧化应激状态下一种重要的去乙酰化酶。H₂S能够调节多种沉默信息调节因子的活性。本研究旨在探究SIRT3在内皮细胞中H₂S抗氧化作用中的作用。
将培养的EA.hy926内皮细胞暴露于过氧化氢（H₂O₂）中，作为氧化应激诱导细胞损伤的模型。GYY4137是一种缓释H₂S供体，可提高细胞活力，降低氧化应激和细胞凋亡，并改善H₂O₂处理后的线粒体功能。H₂S可逆转H₂O₂诱导的丝裂原活化蛋白激酶（MAPK）磷酸化的刺激、SIRT3 mRNA的下调以及超氧化物歧化酶2和异柠檬酸脱氢酶2表达的降低。H₂S还增加了活化蛋白1（AP-1）与SIRT3启动子的结合活性，而在存在特异性AP-1抑制剂SR11302或姜黄素的情况下，这种作用消失。给小鼠注射百草枯会导致内皮依赖性主动脉血管舒张功能缺陷，并增加小鼠主动脉和小肠系膜动脉中的氧化应激，而GYY4137处理可缓解这些情况。在SIRT3基因敲除小鼠中，H₂S的这种血管保护作用消失。
本研究结果凸显了SIRT3在体外和体内H₂S对内皮细胞氧化损伤保护作用中的新作用。
H₂S增强了AP-1与SIRT3启动子的结合活性，从而上调SIRT3表达并最终减轻氧化剂引发的血管内皮功能障碍。《抗氧化与氧化还原信号》24卷，第329 - 343页
