Melatonin ameliorates hypoglycemic stress-induced brain endothelial tight junction injury by inhibiting protein nitration of TP53-induced glycolysis and apoptosis regulator.
Melatonin ameliorates hypoglycemic stress-induced brain endothelial tight junction injury by inhibiting protein nitration of TP53-induced glycolysis and apoptosis regulator.
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褪黑激素通过抑制 TP53 诱导的糖酵解和凋亡调节因子 (TIGAR) 的蛋白质硝化来改善低血糖应激诱导的脑内皮紧密连接损伤。
DOI：
10.1111/jpi.12440
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发表时间：
2017-11
影响因子：
10.3
通讯作者：
Han F
中科院分区：
文献类型：
--
作者：
Wang CK;Ahmed MM;Jiang Q;Lu NN;Tan C;Gao YP;Mahmood Q;Chen DY;Fukunaga K;Li M;Chen Z;Wilcox CS;Lu YM;Qin ZH;Han F
严重低血糖对血管系统有不利影响，但导致紧密连接完整性破坏的分子事件仍不清楚。在这里，我们报告说，微血管完整性显着受损（野生型小鼠的59.41%）在TP 53诱导的糖酵解和凋亡调节因子（TIGAR）转基因小鼠低血糖应激。褪黑素是一种有效的抗氧化剂，在400 nmol/L的剂量下对低血糖应激诱导的脑内皮紧密连接损伤具有保护作用。低浓度葡萄糖应激的内皮细胞的FRET（fluorescence resonance energy transfer）成像数据显示TIGAR与钙调素偶联以促进TIGAR酪氨酸硝化。酪氨酸92突变干扰TIGAR依赖性NADPH生成（减少55.60%），并消除其对人脑微血管内皮细胞紧密连接的保护作用。我们进一步证明，低葡萄糖诱导的occludin和Caludin 5的破坏以及自噬的激活在体外被褪黑素介导的亚硝化应激阻断所消除。总的来说，我们提供了褪黑激素对脑内皮紧密连接保护作用的详细分子机制的信息，并表明这种吲哚对严重低血糖诱导的神经血管损伤具有翻译潜力。
Severe hypoglycemia has a detrimental impact on the cerebrovasculature, but the molecular events that lead to the disruption of the integrity of the tight junctions remain unclear. Here, we report that the microvessel integrity was dramatically compromised (59.41% of wild‐type mice) in TP53‐induced glycolysis and apoptosis regulator (TIGAR) transgenic mice stressed by hypoglycemia. Melatonin, a potent antioxidant, protects against hypoglycemic stress‐induced brain endothelial tight junction injury in the dosage of 400 nmol/L in vitro. FRET (fluorescence resonance energy transfer) imaging data of endothelial cells stressed by low glucose revealed that TIGAR couples with calmodulin to promote TIGAR tyrosine nitration. A tyrosine 92 mutation interferes with the TIGAR‐dependent NADPH generation (55.60% decreased) and abolishes its protective effect on tight junctions in human brain microvascular endothelial cells. We further demonstrate that the low‐glucose‐induced disruption of occludin and Caludin5 as well as activation of autophagy was abrogated by melatonin‐mediated blockade of nitrosative stress in vitro. Collectively, we provide information on the detailed molecular mechanisms for the protective actions of melatonin on brain endothelial tight junctions and suggest that this indole has translational potential for severe hypoglycemia‐induced neurovascular damage.
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影响因子：
11.4
作者：
Bensaad, Karim;Cheung, Eric C.;Vousden, Karen H.
通讯作者：
Vousden, Karen H.
影响因子：
3.9
作者：
ISCHIROPOULOS, H;ZHU, L;BECKMAN, JS
通讯作者：
BECKMAN, JS
DOI：
10.2174/1871527313666140711091400
发表时间：
2014-01-01
影响因子：
3
作者：
Anderson, George;Maes, Michael
通讯作者：
Maes, Michael
影响因子：
3.9
作者：
Blanco, Santos;Hernandez, Raquel;Angeles Peinado, Maria
通讯作者：
Angeles Peinado, Maria
DOI：
10.1016/j.bbrc.2005.11.133
发表时间：
2006-01-27
影响因子：
3.1
作者：
Kago, T;Takagi, N;Takeo, S
通讯作者：
Takeo, S