An Jie, Zhang Chen, Polavarapu Rohini, Zhang Xiaohui, Zhang Xiumei, Yepes Manuel
Institute of Pharmacology, Shandong University School of Medicine, Jinan, China.
Blood. 2008 Oct 1;112(7):2787-94. doi: 10.1182/blood-2008-02-141630. Epub 2008 Jul 15.
Tissue-type plasminogen activator (tPA) is found in the intravascular space and in the central nervous system. The low-density lipoprotein receptor-related protein (LRP) is expressed in neurons and in perivascular astrocytes. During cerebral ischemia, tPA induces the shedding of LRP's extracellular domain from perivascular astrocytes, and this is followed by the development of cerebral edema. Protein kinase B (Akt) is a serine/threonine kinase that plays a critical role not only in cell survival but also in the regulation of the permeability of the blood-brain barrier. We found that, in the early phases of the ischemic insult, the interaction between tPA and LRP induces Akt phosphorylation (pAkt) in perivascular astrocytes and inhibits pAkt in neurons. Coimmunoprecipitation studies indicate that pAkt and LRP's intracellular domain interact in perivascular astrocytes and that this interaction is dependent on the presence of tPA and results in the development of edema. Together, these results indicate that, in the early stages of cerebral ischemia, the interaction between tPA and LRP in perivascular astrocytes induces the activation of a cell signaling event mediated by pAkt that leads to increase in the permeability of the blood-brain barrier.
组织型纤溶酶原激活剂（tPA）存在于血管内空间和中枢神经系统中。低密度脂蛋白受体相关蛋白（LRP）在神经元和血管周围星形胶质细胞中表达。在脑缺血期间，tPA诱导血管周围星形胶质细胞中LRP细胞外结构域的脱落，随后出现脑水肿。蛋白激酶B（Akt）是一种丝氨酸/苏氨酸激酶，不仅在细胞存活中起关键作用，还在血脑屏障通透性的调节中起关键作用。我们发现，在缺血性损伤的早期阶段，tPA与LRP之间的相互作用在血管周围星形胶质细胞中诱导Akt磷酸化（pAkt），并在神经元中抑制pAkt。免疫共沉淀研究表明，pAkt与LRP的细胞内结构域在血管周围星形胶质细胞中相互作用，这种相互作用依赖于tPA的存在并导致水肿的发生。总之，这些结果表明，在脑缺血的早期阶段，血管周围星形胶质细胞中tPA与LRP之间的相互作用诱导了由pAkt介导的细胞信号事件的激活，从而导致血脑屏障通透性增加。
