Contribution of redox-dependent activation of endothelial Nlrp3 inflammasomes to hyperglycemia-induced endothelial dysfunction.
Contribution of redox-dependent activation of endothelial Nlrp3 inflammasomes to hyperglycemia-induced endothelial dysfunction.
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氧化还原依赖性内皮 Nlrp3 炎症小体激活对高血糖诱导的内皮功能障碍的影响
DOI：
10.1007/s00109-016-1481-5
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发表时间：
2016-12
期刊：
影响因子：
--
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Chen Y;Wang L;Pitzer AL;Li X;Li PL;Zhang Y
近年来的研究表明，炎性小体作为一种细胞内机制，启动了经典的精氨酸介导的炎症反应，在心血管疾病的发病机制中起着至关重要的作用。然而，内皮炎性小体的激活是否直接导致细胞功能障碍或组织损伤而不募集炎性细胞尚不清楚。我们探讨了内皮细胞炎性小体激活在介导紧密连接破坏中的作用，紧密连接破坏是导致糖尿病内皮通透性过高的内皮屏障功能障碍的标志性事件。我们使用共聚焦显微镜研究了链脲佐菌素治疗的糖尿病野生型和Nlrp 3基因缺失小鼠冠状动脉中NOD样受体家族pyrin domain containing-3（Nlrp 3）炎性小体的形成和激活以及紧密连接蛋白的表达。我们发现Nlrp 3消融可阻止糖尿病小鼠冠状动脉内皮炎性小体激活和紧密连接解体。类似地，Nlrp 3基因沉默阻止了高糖诱导的小鼠血管内皮细胞（MVECs）紧密连接蛋白的下调。高葡萄糖诱导的紧密连接破坏和随后的内皮渗透性归因于高迁移率族蛋白-1（HMGB 1）的释放增加，其依赖于增强的Nlrp 3炎性体活性。从机制上讲，减少活性氧（ROS）的产生消除了高糖诱导的炎性小体激活，紧密连接破坏和MVEC的内皮细胞通透性过高。总的来说，ROS依赖性激活的内皮Nlrp 3炎症体的高血糖症可能是一个重要的启动机制，导致内皮功能障碍。糖尿病患者内皮细胞紧密连接的破坏需要Nlrp 3炎性小体的参与。高糖通过ROS的产生激活内皮细胞中的Nlrp 3炎性小体。高糖激活内皮细胞炎性小体触发HMGB 1的释放。阻断Nlrp 3/HMGB 1轴抑制高糖诱导的内皮细胞通透性。
AbstractRecent studies indicate that inflammasomes serve as intracellular machinery to initiate classical cytokine-mediated inflammatory responses and play a crucial role in the pathogenesis of cardiovascular diseases. However, whether or not the activation of endothelial inflammasomes directly causes cell dysfunction or tissue injury without recruitment of inflammatory cells is unknown. We explored the role of endothelial cell inflammasome activation in mediating tight junction disruption, a hallmark event of endothelial barrier dysfunction leading to endothelial hyperpermeability in diabetes. We used confocal microscopy to study the formation and activation of NOD-like receptor family pyrin domain containing-3 (Nlrp3) inflammasomes and expression of tight junction proteins in coronary arteries of streptozotocin-treated diabetic wild type andNlrp3gene-deleted mice. We found thatNlrp3ablation prevented inflammasome activation and tight junction disassembly in the coronary arterial endothelium of diabetic mice. Similarly,Nlrp3gene silencing prevented high glucose-induced down-regulation of tight junction proteins in cultured mouse vascular endothelial cells (MVECs). The high glucose-induced tight junction disruption and consequent endothelial permeability were attributed to increased release of the high mobility group box protein-1 (HMGB1), which is dependent on enhanced Nlrp3 inflammasome activity. Mechanistically, reducing reactive oxygen species (ROS) production abolished high glucose-induced inflammasome activation, tight junction disruption, and endothelial hyperpermeability in MVECs. Collectively, the ROS-dependent activation of endothelial Nlrp3 inflammasomes by hyperglycemia may be an important initiating mechanism to cause endothelial dysfunction. These effects could contribute to the early onset of endothelial injury in diabetes.Key messageEndothelial tight junction disruption in diabetes requires Nlrp3 inflammasomes.High glucose activates Nlrp3 inflammasome in endothelial cells via ROS production.Activation of endothelial inflammasome by high glucose triggers release of HMGB1.Blockade of Nlrp3/HMGB1 axis inhibits high glucose-induced endothelial permeability.
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DOI：
10.1016/j.bbamcr.2014.11.012
发表时间：
2015-02
影响因子：
5.1
作者：
Chen, Yang;Li, Xiang;Boini, Krishna M.;Pitzer, Ashley L.;Gulbins, Erich;Zhang, Yang;Li, Pin-Lan
通讯作者：
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影响因子：
4.7
作者：
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影响因子：
7.7
作者：
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通讯作者：
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影响因子：
30.5
作者：
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影响因子：
20.1
作者：
Geraldes P;King GL
通讯作者：
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