The small GTPase Rab26 is involved in multiple processes, such as vesicle-mediated secretion and autophagy. However, the mechanisms and functions of Rab26 in the human pulmonary microvascular endothelial cells (HPMVECs) are not clear. In this study, we thoroughly investigated the role and novel mechanism of Rab26 in permeability and apoptosis of HPMVECs using a self-assembled Rab26 siRNA loaded DNA Y-motif nanoparticle (siRab26-DYM) and Rab26 adenovirus. We found that siRab26-DYM could be efficiently transfected into HPMVECs in a time- and dose-dependent manner. Importantly, the siRab26-DYM nanovector markedly aggravated the LPS-induced apoptosis and hyper-permeability of HPMVECs by promoting the nuclear translocation of Foxo1, and subsequent activation of Toll-like receptor 4 (TLR4) signal pathway. Overexpression of Rab26 by Rab26 adenoviruses partially inactivated LPS-induced TLR4 signaling pathway, suppressed the cell apoptosis and attenuated the hyperpermeability of HPMVECs. These results suggest that the permeability and apoptosis of HPMVECs can be modulated by manipulating Rab26 derived TLR4 signaling pathway, and that Rab26 can be potential therapeutic target for the treatment of vascular diseases related to endothelial barrier functions.

中文翻译：

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Rab26 siRNA加载的DNA纳米载体在肺微血管内皮细胞中对Toll样受体4和细胞屏障功能的调节。

小的GTPase Rab26参与多个过程，例如囊泡介导的分泌和自噬。但是，Rab26在人肺微血管内皮细胞（HPMVEC）中的机制和功能尚不清楚。在这项研究中，我们彻底研究了Rab26在HPMVEC的通透性和凋亡中的作用和新机制，方法是使用自组装的装载Rab26 siRNA的DNA Y-基序纳米颗粒（siRab26-DYM）和Rab26腺病毒。我们发现，siRab26-DYM可以以时间和剂量依赖性方式有效地转染到HPMVECs中。重要的是，siRab26-DYM纳米载体通过促进Foxo1的核易位以及随后激活Toll样受体4（TLR4）信号通路，显着加重了LPS诱导的HPMVECs的凋亡和高通透性。Rab26腺病毒过度表达Rab26会部分灭活LPS诱导的TLR4信号通路，抑制细胞凋亡并减弱HPMVEC的高通透性。这些结果表明，可以通过操纵Rab26衍生的TLR4信号通路来调节HPMVEC的通透性和凋亡，并且Rab26可能是治疗与内皮屏障功能有关的血管疾病的潜在治疗靶标。