HSP27 phosphorylation protects against endothelial barrier dysfunction under burn serum challenge.
HSP27 phosphorylation protects against endothelial barrier dysfunction under burn serum challenge.
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DOI：
10.1016/j.bbrc.2015.04.152
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发表时间：
2015-07
影响因子：
3.1
通讯作者：
Huanbo Sun;Xi Ren;Jie Liu;Xiaowei Guo;Xu-pin Jiang;Dong‐xia Zhang;Yuesheng Huang;Jiaping Zhang
中科院分区：
文献类型：
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作者：
Huanbo Sun;Xi Ren;Jie Liu;Xiaowei Guo;Xu-pin Jiang;Dong‐xia Zhang;Yuesheng Huang;Jiaping Zhang
f -肌动蛋白重排是烧伤引起的内皮屏障功能障碍的早期事件。HSP27是p38 MAPK/MK2通路的靶点，通过磷酸化在肌动蛋白动力学中发挥重要作用。HSP27是否参与烧伤相关内皮屏障功能障碍的问题尚未确定。在这里，我们发现烧伤血清诱导了中央f -肌动蛋白应激纤维的短暂出现，随后在肺内皮单层中形成不规则致密的外周f -肌动蛋白，并伴有HSP27磷酸化的短暂增加，这与p38 MAPK/MK2的持续激活意外冲突。f -肌动蛋白应激纤维的出现和HSP27磷酸化的短暂增加发生在烧伤血清诱导的内皮细胞高通透性之前。过表达模拟磷酸化的HSP27（HSP27(Asp)）可逆转烧伤血清诱导的外周f -肌动蛋白重排，增加中央f -肌动蛋白应激纤维，更重要的是，减轻烧伤血清诱导的内皮细胞高通透性；在HSP27的非磷酸化突变体HSP27（Ala）中没有观察到这种效应。HSP27（Asp）过表达也使单层膜更能抵抗细胞松弛素D（一种能特异性解聚f -肌动蛋白的化学试剂）造成的屏障破坏。进一步的研究表明，在烧伤血清诱导的内皮细胞高通透性过程中，磷酸酶和summoylation抑制MK2活性有助于HSP27磷酸化的钝化。我们的研究确定了HSP27磷酸化是对烧伤血清诱导的内皮屏障功能障碍的保护反应，并表明靶向HSP27伤口是改善烧伤诱导的肺水肿和休克发展的一种有希望的治疗策略。
F-actin rearrangement is an early event in burn-induced endothelial barrier dysfunction. HSP27, a target of p38 MAPK/MK2 pathway, plays an important role in actin dynamics through phosphorylation. The question of whether HSP27 participates in burn-related endothelial barrier dysfunction has not been identified yet. Here, we showed that burn serum induced a temporal appearance of central F-actin stress fibers followed by a formation of irregular dense peripheral F-actin in pulmonary endothelial monolayer, concomitant with a transient increase of HSP27 phosphorylation that conflicted with the persistent activation of p38 MAPK/MK2 unexpectedly. The appearance of F-actin stress fibers and transient increase of HSP27 phosphorylation occurred prior to the burn serum-induced endothelial hyperpermeability. Overexpressing phospho-mimicking HSP27 (HSP27(Asp)) reversed the burn serum-induced peripheral F-actin rearrangement with the augmentation of central F-actin stress fibers, and more importantly, attenuated the burn serum-induced endothelial hyperpermeability; such effects were not observed by HSP27(Ala), a non-phosphorylated mutant of HSP27. HSP27(Asp) overexpression also rendered the monolayer more resistant to barrier disruption caused by Cytochalasin D, a chemical reagent that depolymerizes F-actin specifically. Further study showed that phosphatases and sumoylation-inhibited MK2 activity contributed to the blunting of HSP27 phosphorylation during the burn serum-induced endothelial hyperpermeability. Our study identifies HSP27 phosphorylation as a protective response against burn serum-induced endothelial barrier dysfunction, and suggests that targeting HSP27 wound be a promising therapeutic strategy in ameliorating burn-induced lung edema and shock development.