The ATX-LPA Axis Regulates Vascular Permeability during Cerebral Ischemic-Reperfusion.
The ATX-LPA Axis Regulates Vascular Permeability during Cerebral Ischemic-Reperfusion.
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DOI：
10.3390/ijms23084138
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发表时间：
2022-04-08
影响因子：
5.6
通讯作者：
Panchatcharam, Manikandan
中科院分区：
文献类型：
--
作者：
Bhattarai, Susmita;Sharma, Sudha;Subedi, Utsab;Ara, Hosne;Shum, Alika;Milena, Murov;Bhuiyan, Md Shenuarin;Kidambi, Srivatsan;Sun, Hong;Miriyala, Sumitra;Panchatcharam, Manikandan
内皮通透性是中风治疗中必须解决的主要并发症。研究血脑屏障（BBB）破坏的机制和再灌注后缺氧应激诱导的内皮细胞通透性的管理都是卒中管理的迫切需要。溶血磷脂酸（LPA）是一种对基本细胞功能至关重要的生物活性脂质，在卒中进展期间会导致不利的结局。LPA产生酶自分泌运动因子（ATX）在缺血性卒中中受到调节。我们使用电细胞基质阻抗传感器（ECIS）来测量内皮通透性。使用海马分析仪获得线粒体生物能量学。AR-2探针荧光测定法用于测量ATX活性。LPA增加内皮通透性和减少连接蛋白在小鼠脑微血管内皮细胞（MBMEC）的表达。LPA受体抑制剂Ki 16425和AM 095减弱了LPA诱导的内皮通透性和连接蛋白的变化。LPA显著降低MBMEC的线粒体功能。缺氧再灌注时，脑微血管内皮细胞ATX表达上调（p < 0.05）。在小鼠中风模型中使用ATX抑制剂减弱ATX活性和渗透性。缺氧再灌注时ATX的上调导致脑内皮细胞中LPA的产生，有利于通透性。ATX-LPA-LPAR轴的抑制可以在中风中作为治疗靶点以实现更好的结果。
Endothelial permeability is a major complication that must be addressed during stroke treatment. Study of the mechanisms underlying blood–brain barrier (BBB) disruption and management of the hypoxic stress-induced permeability of the endothelium following reperfusion are both urgently needed for stroke management. Lysophosphatidic acid (LPA), a bioactive lipid essential for basic cellular functions, causes unfavorable outcomes during stroke progression. LPA-producing enzyme autotaxin (ATX) is regulated in ischemic stroke. We used an electrical cell-substrate impedance sensor (ECIS) to measure endothelial permeability. Mitochondrial bioenergetics were obtained using a Seahorse analyzer. AR-2 probe fluorescence assay was used to measure ATX activity. LPA increased endothelial permeability and reduced junctional protein expression in mouse brain microvascular endothelial cells (MBMEC). LPA receptor inhibitors Ki16425 and AM095 attenuated the LPA-induced changes in the endothelial permeability and junctional proteins. LPA significantly diminished mitochondrial function in MBMEC. ATX was upregulated (p < 0.05) in brain microvascular endothelial cells under hypoxic reperfusion. ATX activity and permeability were attenuated with the use of an ATX inhibitor in a mouse stroke model. The upregulation of ATX with hypoxic reperfusion leads to LPA production in brain endothelial cells favoring permeability. Inhibition of the ATX–LPA–LPAR axis could be therapeutically targeted in stroke to achieve better outcomes.
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影响因子：
11.4
作者：
Chandra M;Escalante-Alcalde D;Bhuiyan MS;Orr AW;Kevil C;Morris AJ;Nam H;Dominic P;McCarthy KJ;Miriyala S;Panchatcharam M
通讯作者：
Panchatcharam M
DOI：
10.1084/jem.20171406
发表时间：
2017-11-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Montagne A;Zhao Z;Zlokovic BV
通讯作者：
Zlokovic BV
影响因子：
4.6
作者：
Cai J;Wei J;Li S;Suber T;Zhao J
通讯作者：
Zhao J
影响因子：
2.6
作者：
Butler, Jarrhett;Heidari, Parisa;Leigh, Richard
通讯作者：
Leigh, Richard
影响因子：
7.2
作者：
Daneman, Richard;Prat, Alexandre
通讯作者：
Prat, Alexandre