Modulation of HSP27 alters hypoxia-induced endothelial permeability and related signaling pathways.
Modulation of HSP27 alters hypoxia-induced endothelial permeability and related signaling pathways.
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DOI：
10.1002/jcp.21773
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发表时间：
2009-09
影响因子：
5.6
通讯作者：
Kayyali, Usamah S.
中科院分区：
文献类型：
--
作者：
Liu, Tiegang;Guevara, Oscar E.;Warburton, Rod R.;Hill, Nicholas S.;Gaestel, Matthias;Kayyali, Usamah S.
本文描述了肺动脉微血管内皮细胞（RPMEC）单层通透性是如何因缺氧而升高的，以及HSP27磷酸化所起的作用。p38 MAP激酶激活导致HSP27磷酸化，先前我们的实验室已经证明可以改变RPMEC的肌动蛋白细胞骨架和栓系特性。这种效应不依赖于缺氧诱导的收缩力，收缩力依赖于rock而不是hsp27。本研究的结果表明，HSP27磷酸化的增加不仅不是缺氧诱导的通透性的基础，而且实际上可能会增强内皮屏障。缺氧导致RPMEC之间形成间隙，增加MLC2磷酸化。抑制MLC2磷酸酶的MYPT1的磷酸化也在缺氧时增加。此外，改变局灶粘附信号的FAK磷酸化在缺氧时增加。过表达磷酸化模拟HSP27 (pmHSP27)，诱导显著的肌动蛋白应激纤维形成，令人惊讶地使RPMEC抵抗缺氧或tgf β诱导的渗透性。抗pmHSP27的siRNA逆转了pmHSP27过表达细胞中肌动蛋白应激纤维的增加，破坏pmHSP27过表达的RPMEC中的肌动蛋白应激纤维使其更容易缺氧。最后，缺氧诱导的间隙形成以及MLC2、MYPT1和FAK的磷酸化几乎被RPMEC中过表达pmHSP27所消除。pmHSP27过表达的这些影响可能表现为细胞骨架可塑性降低和栓系增加，从而抵消了通透性诱导的收缩性。因此，缺氧激活了两条途径，一条导致收缩性和增加渗透性，另一条导致肌动蛋白应力纤维，更强的粘附性和降低渗透性。改变HSP27磷酸化，使通透性降低，可能是控制内皮屏障功能障碍的目标。
This manuscript describes how the permeability of pulmonary artery microvascular endothelial cell (RPMEC) monolayer is elevated by hypoxia and the role played by HSP27 phosphorylation. p38 MAP kinase activation leading to HSP27 phosphorylation was previously shown by our laboratory to alter the actin cytoskeleton and tethering properties of RPMEC. This effect was independent of hypoxia-induced contractility which was ROCK-dependent rather than HSP27-dependent. Results described here show that increased HSP27 phosphorylation not only does not underlie hypoxia-induced permeability, but may actually augment the endothelial barrier. Hypoxia causes gap formation between RPMEC and increases MLC2 phosphorylation. The phosphorylation of MYPT1, which inhibits MLC2 phosphatase, is also increased in hypoxia. In addition, FAK phosphorylation, which alters focal adhesion signaling, is increased in hypoxia. Overexpressing phospho-mimicking HSP27 (pmHSP27), which induces significant actin stress fiber formation, surprisingly renders RPMEC resistant to hypoxia- or TGFβ-induced permeability. siRNA against pmHSP27 reverses the increased actin stress fiber formation in pmHSP27-overexpressing cells, and disrupting actin stress fibers in pmHSP27-overexpressing RPMEC renders them more susceptible to hypoxia. Finally, hypoxia-induced gap formation, as well as phosphorylation of MLC2, MYPT1 and FAK are almost abolished by overexpressing pmHSP27 in RPMEC. These effects of pmHSP27 overexpression might represent decreased cytoskeletal plasticity and increased tethering which counteracts permeability-inducing contractility. Thus hypoxia activates two pathways one leading to contractility and increased permeability, the other leading to actin stress fibers, stronger adhesion, and reduced permeability. Altering HSP27 phosphorylation, which tips the balance towards decreased permeability, might be targeted in managing endothelial barrier dysfunction.
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作者：
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通讯作者：
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