RhoA/ROCK-2 Pathway Inhibition and Tight Junction Protein Upregulation by Catalpol Suppresses Lipopolysaccaride-Induced Disruption of Blood-Brain Barrier Permeability.
RhoA/ROCK-2 Pathway Inhibition and Tight Junction Protein Upregulation by Catalpol Suppresses Lipopolysaccaride-Induced Disruption of Blood-Brain Barrier Permeability.
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梓醇对 RhoA/ROCK-2 通路的抑制和紧密连接蛋白的上调可抑制脂多糖诱导的血脑屏障通透性破坏
DOI：
10.3390/molecules23092371
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发表时间：
2018-09-17
期刊：
影响因子：
--
通讯作者：
Zhu H
中科院分区：
文献类型：
--
作者：
Feng S;Zou L;Wang H;He R;Liu K;Zhu H
脂多糖直接或间接损伤脑微血管内皮细胞，破坏细胞间紧密连接，引起血脑屏障(BBB)通透性改变。梓醇对内毒素损伤有保护作用，但是否对内毒素引起的血脑屏障通透性损伤有保护作用及其机制尚不清楚。预防使用梓醇(5 mg/kg，静脉注射)连续3天，通过减少伊文思蓝(EB)渗漏和恢复C57小鼠的紧密连接，逆转了内毒素诱导的血脑屏障损伤。梓醇与脂多糖联合作用可增加BMEC的存活率，减少其分泌内皮素-1、肿瘤坏死因子-Α和IL-6，并呈时间依赖性地改善细胞的跨膜电阻，增加荧光素钠通透系数。此外，透射电子显微镜显示了梓醇对紧密连接的保护作用。荧光染色显示梓醇逆转了细胞骨架蛋白F-肌动蛋白的重排，上调了紧密连接蛋白Claudin-5和ZO-1的表达，ZO-1、ZO-2、ZO-3、Claudin-5和occludin的mRNA和蛋白表达水平进一步证明了这一点。此外，梓醇同时下调RhoA/ROCK2信号通路中的关键蛋白RhoA和ROCK2的mRNA和蛋白水平。本研究表明，梓醇通过抑制RhoA/ROCK2信号通路，逆转BMECs细胞骨架肌动蛋白的解聚，阻止连接蛋白claudin-5、occludin和ZO-1的下调，减少内皮素-1和炎性细胞因子的分泌，最终减轻内毒素诱导的血脑屏障通透性增加。
Lipopolysaccaride (LPS) directly or indirectly injures brain microvascular endothelial cells (BMECs) and damages the intercellular tight junction that gives rise to altered blood-brain barrier (BBB) permeability. Catalpol plays a protective role in LPS-induced injury, but whether catalpol protects against LPS-caused damage of BBB permeability and the underlying mechanism remain to be delineated. Prophylactic protection with catalpol (5 mg/kg, i.v.) consecutively for three days reversed the LPS-induced damage of BBB by decreased Evans Blue (EB) leakage and restored tight junctions in C57 mice. Besides, catalpol co-administrated with LPS increased BMECs survival, decreased their endothelin-1, TNF-Α and IL-6 secretion, improved transmembrane electrical resistance in a time-dependent manner, and in addition increased the fluorescein sodium permeability coefficient of BMECs. Also, transmission electron microscopy showed catalpol protective effects on tight junctions. Fluorescence staining displayed that catalpol reversed the rearrangement of the cytoskeleton protein F-actin and upregulated the tight junction protein of claudin-5 and ZO-1, which have been further demonstrated by the mRNA and protein expression levels of ZO-1, ZO-2, ZO-3, claudin-5, and occludin. Moreover, catalpol concurrently downregulated the mRNA and protein levels of RhoA, and ROCK2, the critical proteins in the RhoA/ROCK2 signaling pathway. This study thus indicated that catalpol, via inhibition of the RhoA/ROCK2 signaling pathway, reverses the disaggregation of cytoskeleton actin in BMECs and prevents down-regulation of junctional proteins, such as claudin-5, occludin, and ZO-1, and decreases endothelin-1 and inflammatory cytokine secretion, eventually alleviating the increase in LPS-induced BBB permeability.
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DOI：
10.1016/j.bbrc.2012.07.063
发表时间：
2012-08-24
影响因子：
3.1
作者：
He, Fang;Yin, Fei;Peng, Jing
通讯作者：
Peng, Jing
影响因子：
3.4
作者：
Capaldo, Christopher T.;Nusrat, Asma
通讯作者：
Nusrat, Asma
影响因子：
5
作者：
Hu, Lingai;Sun, Yukun;Hu, Jian
通讯作者：
Hu, Jian
影响因子：
6.1
作者：
Freeman BD;Machado FS;Tanowitz HB;Desruisseaux MS
通讯作者：
Desruisseaux MS
影响因子：
3.7
作者：
Niego B;Lee N;Larsson P;De Silva TM;Au AE;McCutcheon F;Medcalf RL
通讯作者：
Medcalf RL