Lysosome-Membrane Fusion Mediated Superoxide Production in Hyperglycaemia-Induced Endothelial DysfunctionReport as inadecuate




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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.



Author: Jun-Xiang Bao , Hui Chang , Yong-Gang Lv , Jin-Wen Yu, Yun-Gang Bai, Huan Liu, Yue Cai, Ling Wang , Jin Ma , Yao-Ming Chang

Source: http://plos.srce.hr/



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