Nagai Nobuo, Okada Kiyotaka, Kawao Naoyuki, Ishida Chikako, Ueshima Shigeru, Collen Desire, Matsuo Osamu
Department of Physiology, Kinki University School of Medicine, Ohnohigashi 377-2, Osakasayama, Osaka 589-8511, Japan.
Neurosci Lett. 2008 Feb 13;432(1):46-9. doi: 10.1016/j.neulet.2007.12.004. Epub 2007 Dec 8.
Urokinase-type plasminogen activator receptor (uPAR) is a key component of the plasminogen activation system at the cell surface. Recent studies showed that uPAR is expressed in the ischemic damaged brain, suggesting its involvement in brain damage. In this study, we evaluated the role of uPAR in ischemic brain damage induced by permanent middle cerebral artery (MCA) occlusion in mice with genetic deficiency of uPAR (uPAR(-/-)) or of uPA (uPA(-/-)). Brain damage at 3 days was smaller in uPAR(-/-) mice (4.5+/-1.0mm(3)) than in littermate wild-type mice (uPAR(+/+)) (9.1+/-1.8mm(3), p<0.05), whereas it was comparable in uPA(-/-) (8.0+/-4.1mm(3)) and uPA(+/+) (6.9+/-2.6mm(3)) mice. uPAR expression was upregulated in the ipsilateral cerebral cortex within 12h, and remained elevated for up to 3 days. At 1 or 2 days after MCA occlusion, uPAR expression was selectively localized in vessels at the border of the damaged area. These findings suggest that uPAR expressed by endothelial cells augments the ischemic brain damage via a uPA-independent mechanism.
尿激酶型纤溶酶原激活物受体（uPAR）是细胞表面纤溶酶原激活系统的关键组成部分。最近的研究表明，uPAR在缺血性脑损伤中表达，提示其参与脑损伤过程。在本研究中，我们评估了uPAR在永久性大脑中动脉（MCA）闭塞诱导的缺血性脑损伤中的作用，实验采用uPAR基因缺陷（uPAR(-/-)）或尿激酶型纤溶酶原激活物（uPA）基因缺陷（uPA(-/-)）的小鼠。3天时，uPAR(-/-)小鼠的脑损伤体积（4.5±1.0mm³）小于同窝野生型小鼠（uPAR(+/+)）（9.1±1.8mm³，p<0.05），而uPA(-/-)小鼠（8.0±4.1mm³）和uPA(+/+)小鼠（6.9±2.6mm³）的脑损伤体积相当。uPAR表达在12小时内在同侧大脑皮层上调，并持续升高至3天。MCA闭塞后1或2天，uPAR表达选择性定位于损伤区域边界的血管。这些发现表明，内皮细胞表达的uPAR通过不依赖uPA的机制加剧缺血性脑损伤。
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