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首页> 外文期刊>Cellular Signalling >Critical role of autophagy regulator Beclin1 in endothelial cell inflammation and barrier disruption
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Critical role of autophagy regulator Beclin1 in endothelial cell inflammation and barrier disruption

机译：自噬调节剂BECLIN1在内皮细胞炎症和屏障中断的关键作用

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Recent studies have implicated autophagy in several inflammatory diseases involving aberrant endothelial cell (EC) responses, such as acute lung injury (ALI). However, the mechanistic basis for a role of autophagy in EC inflammation and permeability remain poorly understood. In this study, we impaired autophagy by silencing the essential Beclin1 autophagy gene in human pulmonary artery EC. This resulted in reduced expression of proinflammatory genes in response to thrombin, a procoagulant and proinflammatory mediator whose concentration is elevated in many diseases including sepsis and ALI. These (Beclin1-depleted) cells also displayed a marked decrease in NF-kappa B activity secondary to impaired DNA binding of RelA/p65 in the nucleus, but exhibited normal I kappa B alpha degradation in the cytosol. Further analysis showed that Beclin1 knockdown was associated with impaired RelA/p65 translocation to the nucleus. Additionally, Beclin1 knockdown attenuated thrombin-induced phosphorylation of ReIA/p65 at Ser(536), a critical event necessary for the transcriptional activity of RelA/p65. Beclinl silencing also protected against thrombin-induced EC barrier disruption by preventing the loss of VE-cadherin at adherens junctions. Moreover, Beclin1 knockdown reduced thrombin-induced phosphorylation/inactivation of actin depolymerizing protein Cofilin1 and thereby actin stress fiber formation required for EC permeability as well as RelA/p65 nuclear translocation. Together, these data identify Beclin1 as a novel mechanistic link between autophagy and EC dysfunction (inflammation and permeability).
机译：最近的研究在涉及异常内皮细胞（EC）反应的几种炎症疾病中具有含有自噬的，例如急性肺损伤（ALI）。然而，在EC炎症和渗透率中自噬作用的机械基础仍然明白很差。在这项研究中，我们通过沉默于人肺动脉EC中的必需BECLIN1自噬基因而受到自噬。这导致蛋白酶响应于凝血酶，诱导剂和初炎介质的表达减少，其浓度在许多疾病中升高，包括败血症和阿里。这些（BECLIN1-FEEPLETED）细胞也显示出次级的NF-KAPPA B活性的显着降低，以在细胞核中扰动RERA / p65的DNA结合受损，但在细胞溶溶胶中表现出正常的I KappaBα降解。进一步的分析表明，BECLIN1敲低与核的Rela / P65易位受损相关。另外，BECLIN1敲低凝血酶诱导的SER（536）的REIA / P65的磷酸化，这是RelA / P65转录活性所需的关键事件。 Beclinl沉默也通过防止粘附结的丧失丧失粘土蛋白丧失来保护凝血酶诱导的EC屏障破坏。此外，BECLIN1敲低降低凝血酶诱导的肌动蛋白解聚蛋白COFILIN1的磷酸化/灭活，从而肌蛋白应力纤维形成EC渗透率以及RELA / P65核易位。这些数据一起识别Beclin1作为自噬和EC功能障碍（炎症和渗透率）之间的新型机制联系。

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