Lysosome-membrane fusion mediated superoxide production in hyperglycaemia-induced endothelial dysfunction.
Lysosome-membrane fusion mediated superoxide production in hyperglycaemia-induced endothelial dysfunction.
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高血糖诱导的内皮功能障碍中溶酶体膜融合介导的超氧化物产生
DOI：
10.1371/journal.pone.0030387
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Chang YM
中科院分区：
文献类型：
--
作者：
Bao JX;Chang H;Lv YG;Yu JW;Bai YG;Liu H;Cai Y;Wang L;Ma J;Chang YM
在细胞凋亡刺激下内皮细胞氧化应激形成过程中，溶酶体胞吐和与细胞膜的融合是至关重要的。我们研究了它在高血糖诱导的内皮功能障碍中的作用。溶酶体膜标记物LAMP1在细胞膜上的表达和溶酶体标志酶进入培养基内表明溶酶体膜融合。我们还检测了神经酰胺的产生，脂筏(LRs)的聚集，gp91Phox的共定位，NADPH氧化酶亚基(NOX)到LRS簇，超氧化物(O2)。人脐静脉内皮细胞(HUVEC)的生成和一氧化氮(NO)含量，以及大鼠离体主动脉内皮依赖的NO介导的血管扩张。与正常葡萄糖(5.6mmoL/L，Ctrl)孵育相比，高糖(22mmoL/L，HG)可促进HUVEC溶酶体膜融合，表现为细胞膜表面LAMP1蛋白含量显著增加，培养液中溶酶体标记酶活性增强。HG孵育还诱导了神经酰胺的生成、LRs的聚集和gp91Phox对LRs簇的共定位，这被证明是介导HG诱导的O2的机制。-在HUVEC中形成，没有枯竭。在功能上，HG孵育后，血管内皮依赖的NO介导的血管扩张作用明显减弱。此外，HG诱导的效应包括神经酰胺的产生，LRs的聚集，gp91Phox对LRs簇的共定位，O2。抑制溶酶体-膜融合可显著抑制内皮细胞的形成和内皮功能障碍。我们认为，高血糖所致的内皮损伤与溶酶体-膜融合以及随后的LRs聚集、LRs-NOX平台的形成和O2密切相关。-生产。
Lysosomal exocytosis and fusion to cellular membrane is critical in the oxidative stress formation of endothelium under apoptotic stimulus. We investigated the role therein of it in hyperglycaemia-induced endothelial dysfunction. The lysosome-membrane fusion was shown by the expression of lamp1, the lysosomal membrane marker, on cellular membrane and the transportation of lysosomal symbolic enzymes into cultural medium. We also examined the ceramide production, lipid rafts (LRs) clustering, colocalization of gp91phox, a NADPH oxidase subunit (NOX) to LRs clusters, superoxide (O2 . -) formation and nitric oxide (NO) content in human umbilical vein endothelial cells (HUVEC) and the endothelium-dependent NO-mediated vasodilation in isolated rat aorta. As compared to normal glucose (5.6 mmol/l, Ctrl) incubation, high glucose (22 mmol/l, HG) exposure facilitated the lysosome-membrane fusion in HUVEC shown by significantly increased quantity of lamp1 protein on cellular membrane and enhanced activity of lysosomal symbolized enzymes in cultural medium. HG incubation also elicited ceramide generation, LRs clustering and gp91phox colocalization to LRs clusters which were proved to mediate the HG induced O2 . - formation and NO depletion in HUVEC. Functionally, the endothelium-dependent NO-mediated vasodilation in aorta was blunted substantially after HG incubation. Moreover, the HG-induced effect including ceramide production, LRs clustering, gp91phox colocalization to LRs clusters, O2 . - formation and endothelial dysfunction could be blocked significantly by the inhibition of lysosome-membrane fusion. We propose that hyperglycaemia-induced endothelial impairment is closely related to the lysosome-membrane fusion and the following LRs clustering, LRs-NOX platforms formation and O2 . - production.
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