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【Endocrinology】抑制NF-kB或Bax可以预防胰岛细胞内
Pancreatic islet β-cell death by apoptosis has been implicated in the pathogenesis of type 1 diabetes mellitus (T1DM) and T2DM (1, 2, 3) by causing absolute or relative insulin deficiency, respectively. Histology of islets from both types of diabetic patients shows different degrees of inflammation with the presence of immune cell infiltration, proapoptotic cytokines, and apoptotic cells (4, 5). Accumulating evidence suggests that endoplasmic reticulum (ER) stress, a cellular response triggered by disturbance of the ER homeostasis and accumulation of unfolded proteins, contributes to β-cell death in both T1DM and T2DM (6, 7, 8, 9, 10, 11).
NO exposure has previously been associated with ER Ca2+ depletion and ER stress by a mechanism that might involve down-regulation of SERCA2b expression (11) and tyrosine nitrosylation within the channel-like domain of SERCA2 proteins (21) or the Ca2+-releasing ryanodine receptors (21, 31, 32) in insulin-producing β-cells, but the direct role of NO in ER stress-induced signaling is unclear. On the other hand, protein misfolding has been suggested to cause reactive oxygen species (ROS) formation through repetitive folding attempts elicited by increased UPR-mediated chaperone activity (33, 34). Furthermore, Ca2+ released from stressed ER can induce mitochondrial ROS production via depolarization of the inner mitochondrial membrane (34). Additionally, ER stress has been shown to cause NO formation via inducible NO synthase (iNOS) expression in a mouse embryonic fibroblast cell line (35, 36), suggesting that ROS/reactive nitrogen species (RNS) generation and ER stress are closely linked events.
In this study, we aimed to clarify the role of ER stress in NO-induced β-cell apoptosis and whether this differs from apoptosis mediated by ER stress caused by Ca2+ depletion. Using this approach, we presently disclosed different kinetics and mediators of NO- and ER stress-induced signaling and apoptosis in insulin-producing cells.
Accumulating evidence suggests that endoplasmic reticulum (ER) stress by mechanisms that include ER Ca2+ depletion via NO-dependent down-regulation of sarcoendoplasmic reticulum Ca2+ ATPase 2b (SERCA2b) contributes to β-cell death in type 1 diabetes. To clarify whether the molecular pathways elicited by NO and ER Ca2+ depletion differ, we here compare the direct effects of NO, in the form of the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP), with the effects of SERCA2 inhibitor thapsigargin (TG) on MAPK, nuclear factor B (NF, Bcl-2 proteins, ER stress, and apoptosis. Exposure of INS-1E cells to TG or SNAP caused caspase-3 cleavage and apoptosis. Both TG and SNAP induced activation of the proapoptotic transcription factor CCAAT/enhancer-binding protein homologous protein (CHOP). However, other classical ER stress-induced markers such as up-regulation of ER chaperone Bip and alternative splicing of the transcription factor Xbp-1 were exclusively activated by TG. TG exposure caused NFB activation, as assessed by IB degradation and NFB DNA binding. Inhibition of NFB or the Bcl-2 family member Bax pathways protected β-cells against TG- but not SNAP-induced β-cell death. These data suggest that NO generation and direct SERCA2 inhibition cause two quantitative and qualitative different forms of ER stress. In contrast to NO, direct ER stress induced by SERCA inhibition causes activation of ER stress signaling pathways and elicit proapoptotic signaling via NFB and Bax. 本人已认领该文编译，48小时后若未提交译文，请其他战友自由认领。
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作者:admin@医学,生命科学 2010-11-20 17:11
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