Hydrogen Sulphide modulating mitochondrial morphology to promote mitophagy in endothelial cells under high-glucose and high-palmitate.
Hydrogen Sulphide modulating mitochondrial morphology to promote mitophagy in endothelial cells under high-glucose and high-palmitate.
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硫化氢调节线粒体形态以促进高葡萄糖和高棕榈酸下内皮细胞的线粒体自噬
DOI：
10.1111/jcmm.13223
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发表时间：
2017-12
影响因子：
5.3
通讯作者：
Zhang W
中科院分区：
文献类型：
--
作者：
Liu N;Wu J;Zhang L;Gao Z;Sun Y;Yu M;Zhao Y;Dong S;Lu F;Zhang W
内皮细胞功能障碍是2型糖尿病血管并发症的主要原因之一。硫化氢(H_2S)具有抗氧化作用，但在高血糖和高脂血症条件下对血管内皮细胞线粒体动力学和有丝分裂的调节尚不清楚。用40 mM葡萄糖和2 0 0μM棕榈酸酯处理大鼠主动脉内皮细胞，以10 0μM NaHS作为外源性H 2S供体，模拟高血糖、高脂血症状态下的内皮细胞。首先，我们证明了高糖和棕榈酸降低了RAECs中H_2S的产生和CSE的表达。在高糖和棕榈酸作用下，证明了H_2S对血管内皮细胞的抗氧化作用，降低了线粒体ROS水平。我们还发现，在高糖和棕榈酸作用下，外源硫化氢能抑制血管内皮细胞线粒体的凋亡。用Mito Tracker和透射电子显微镜检测发现，与高糖和高棕榈酸组相比，外源H_2S减少了线粒体片段，显著降低了p-DRP-1/DRP-1和Fis1的表达，而通过透射电子显微镜检测发现，外源H_2S增加了线粒体的吞噬作用。我们通过免疫沉淀和免疫染色实验证明，外源H_2S促进了PINK1对Parkin的募集，进而泛素化丝裂原蛋白2(Mfn2)，从而阐明了外源H_2S促进有丝分裂吞噬的机制。Parkin siRNA抑制Mfn2、Nix和LC3B的表达，从而消除了有丝分裂吞噬作用。综上所述，外源H_2S可通过抑制氧化应激、减少线粒体片断和促进有丝分裂来保护高糖和棕榈酸诱导的血管内皮细胞的凋亡。基于这些结果，我们提出了H_2S保护血管内皮细胞的新机制，这可能为2型糖尿病血管并发症的治疗提供新的策略。
Endothelial cell dysfunction is one of the main reasons for type II diabetes vascular complications. Hydrogen sulphide (H2S) has antioxidative effect, but its regulation on mitochondrial dynamics and mitophagy in aortic endothelial cells under hyperglycaemia and hyperlipidaemia is unclear. Rat aortic endothelial cells (RAECs) were treated with 40 mM glucose and 200 μM palmitate to imitate endothelium under hyperglycaemia and hyperlipidaemia, and 100 μM NaHS was used as an exogenous H2S donor. Firstly, we demonstrated that high glucose and palmitate decreased H2S production and CSE expression in RAECs. Then, the antioxidative effect of H2S was proved in RAECs under high glucose and palmitate to reduce mitochondrial ROS level. We also showed that exogenous H2S inhibited mitochondrial apoptosis in RAECs under high glucose and palmitate. Using Mito Tracker and transmission electron microscopy assay, we revealed that exogenous H2S decreased mitochondrial fragments and significantly reduced the expression of p‐Drp‐1/Drp‐1 and Fis1 compared to high‐glucose and high‐palmitate group, whereas it increased mitophagy by transmission electron microscopy assay. We demonstrated that exogenous H2S facilitated Parkin recruited by PINK1 by immunoprecipitation and immunostaining assays and then ubiquitylated mitofusin 2 (Mfn2), which illuminated the mechanism of exogenous H2S on mitophagy. Parkin siRNA suppressed the expression of Mfn2, Nix and LC3B, which revealed that it eliminated mitophagy. In summary, exogenous H2S could protect RAECs against apoptosis under high glucose and palmitate by suppressing oxidative stress, decreasing mitochondrial fragments and promoting mitophagy. Based on these results, we proposed a new mechanism of H2S on protecting endothelium, which might provide a new strategy for type II diabetes vascular complication.
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发表时间：
2015-04-13
期刊：
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