EETs reduces LPS-induced hyperpermeability by targeting GRP78 mediated Src activation and subsequent Rho/ROCK signaling pathway.
EETs reduces LPS-induced hyperpermeability by targeting GRP78 mediated Src activation and subsequent Rho/ROCK signaling pathway.
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EET 通过靶向 GRP78 介导的 Src 激活和随后的 Rho/ROCK 信号通路来降低 LPS 诱导的通透性过高
DOI：
10.18632/oncotarget.17331
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发表时间：
2017-08-01
期刊：
影响因子：
--
通讯作者：
Tu L
中科院分区：
文献类型：
--
作者：
Dong R;Hu D;Yang Y;Chen Z;Fu M;Wang DW;Xu X;Tu L
内皮屏障的完整性是脓毒症所致急性肺损伤预后的决定因素。花生四烯酸的代谢产物环氧二十碳三烯酸(EETs)在多种致病状态下均具有保护作用，但EETs是否具有增强内皮屏障的作用及其机制仍有待进一步研究。在这里，我们发现，内皮特异性细胞色素P450环氧合酶2J2过表达和可溶性环氧化物水解酶(SEH)抑制剂TPPU增加了EETS水平，降低了脂多糖诱导的体内内皮高通透性，同时改善了脓毒症小鼠的存活率。此外，在体外研究中，sEH抑制剂Auda和11，12-EET也能降低血管内皮细胞的高通透性。重要的是，相关的机制与减少GRP78-Src相互作用和ROS的产生，从而降低RhoA/ROCK的激活，最终降低VE-钙粘蛋白和肌球蛋白轻链(MLC)的磷酸化有关。因此，CYP2J2-EETs对RhoA依赖的细胞骨架结构的调节导致血管通透性的可逆性改变至关重要，这可能有助于开发新的治疗方法来治疗肺水肿和其他由血管通透性异常引起的疾病。
Integrity of endothelial barrier is a determinant of the prognosis in the acute lung injury caused by sepsis. The epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid, exhibit protective effects in various pathogenic states, however, whether EETs play a role in endothelial barrier enhancement and the involved mechanisms remain to be investigated. Here, we show that increased EETs level by endothelial specific cytochrome P450 epoxygenase 2J2 over-expression and soluble epoxide hydrolase (sEH) inhibitor TPPU reduced lipopolysaccharide-induced endothelial hyper-permeability in vivo, accompanied by improved survival of septic mice. In addition, sEH inhibitor AUDA and 11,12-EET also decreased endothelial hyper-permeability in the in-vitro study. Importantly, the relative mechanisms were associated with reduced GRP78-Src interaction and ROS production, and subsequently reduced RhoA/ROCK activation, and eventually decreased VE-cadherin and myosin light chain (MLC) phosphorylation. Thus CYP2J2-EETs is crucial for RhoA-dependent regulation of cytoskeletal architecture leading to reversible changes in vascular permeability, which may contribute to the development of new therapeutic approaches for pulmonary edema and other diseases caused by abnormal vascular permeability.
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影响因子：
20.1
作者：
Naikawadi RP;Cheng N;Vogel SM;Qian F;Wu D;Malik AB;Ye RD
通讯作者：
Ye RD
影响因子：
5
作者：
Deng Y;Theken KN;Lee CR
通讯作者：
Lee CR
影响因子：
4.8
作者：
Adam, Alejandro P.;Sharenko, Amy L.;Vincent, Peter A.
通讯作者：
Vincent, Peter A.
DOI：
10.1152/ajplung.00202.2009
发表时间：
2010-11-01
影响因子：
4.9
作者：
Birukova, Anna A.;Xing, Junjie;Birukov, Konstantin G.
通讯作者：
Birukov, Konstantin G.
DOI：
10.1152/ajplung.00374.2013
发表时间：
2014-04-01
影响因子：
4.9
作者：
Lee, Intae;Dodia, Chandra;Fisher, Aron B.
通讯作者：
Fisher, Aron B.