Leung Justin W C, Chung Stephen S M, Chung Sookja K
Department of Anatomy, The University of Hong Kong, HKSAR, China.
Brain Res. 2009 Apr 17;1266:121-9. doi: 10.1016/j.brainres.2009.01.070. Epub 2009 Feb 20.
Endothelin-1 (ET-1) is up-regulated in the endothelial cells and astrocytes under ischemia. Transgenic mice with astrocytic ET-1 over-expression (GET-1) showed more severe neurological deficit and larger infarct after transient middle cerebral artery occlusion (MCAO). Here, the significance of endothelial ET-1 in ischemic brain injury was investigated using transgenic mice with the endothelial ET-1 over-expression (TET-1). Increased ET-1 level was observed in the TET-1 brain infarct core after transient MCAO. ET(A) receptor expression was induced in the penumbra and ET(A) antagonist (A-147627) partially normalized the infarct volume and neurological deficit. In the infarct core of TET-1 brain, superoxide, nitrotyrosine, and gp91(phox) levels were increased. TET-1 brain displayed increased matrix metalloproteinase-2 expression, water content, immunoglobulin leakage and decreased occludin level in the ipsilateral hemisphere indicative of BBB breakdown and hemispheric edema. Interestingly, AQP-4 expression was increased in the penumbra of TET-1 brain following transient MCAO leading to the water accumulation. Taken together, endothelial ET-1 over-expression and ETA receptor activation contributes to the increased oxidative stress, water accumulation and BBB breakdown after transient MCAO leading to more severe neurological deficit and increased infarct.
内皮素 -1（ET -1）在缺血状态下的内皮细胞和星形胶质细胞中上调。星形胶质细胞ET -1过表达的转基因小鼠（GET -1）在短暂性大脑中动脉闭塞（MCAO）后表现出更严重的神经功能缺损和更大的梗死灶。在此，利用内皮ET -1过表达的转基因小鼠（TET -1）研究了内皮ET -1在缺血性脑损伤中的意义。短暂性MCAO后，在TET -1脑梗死核心区观察到ET -1水平升高。在半暗带诱导ET(A)受体表达，ET(A)拮抗剂（A -147627）可部分使梗死体积和神经功能缺损恢复正常。在TET -1脑梗死核心区，超氧化物、硝基酪氨酸和gp91(phox)水平升高。TET -1脑在同侧半球显示基质金属蛋白酶 -2表达增加、含水量增加、免疫球蛋白渗漏以及闭合蛋白水平降低，表明血脑屏障破坏和半球水肿。有趣的是，短暂性MCAO后，TET -1脑半暗带中AQP -4表达增加导致积水。综上所述，内皮ET -1过表达和ETA受体激活导致短暂性MCAO后氧化应激增加、积水和血脑屏障破坏，进而导致更严重的神经功能缺损和梗死增加。
