Tissue inhibitor of matrix metalloproteinase-1 mediates erythropoietin-induced neuroprotection in hypoxia ischemia.
Tissue inhibitor of matrix metalloproteinase-1 mediates erythropoietin-induced neuroprotection in hypoxia ischemia.
复制标题
DOI：
10.1016/j.nbd.2011.05.020
复制
发表时间：
2011-10
影响因子：
6.1
通讯作者：
Tang, Jiping
中科院分区：
文献类型：
--
作者：
Souvenir, Rhonda;Fathali, Nancy;Ostrowski, Robert P.;Lekic, Tim;Zhang, John H.;Tang, Jiping
以往的研究表明，促红细胞生成素（EPO）在体内和体外缺氧缺血模型中均具有神经保护作用。然而，这些研究具有有限的临床翻译，因为潜在的机制仍不清楚，参与EPO诱导的神经保护的关键分子仍有待确定。本研究探讨了基质金属蛋白酶组织抑制剂-1（TIMP-1）及其上游调节信号分子Janus激酶-2（JAK-2）是否在EPO诱导的神经保护中起关键作用。缺氧缺血（HI）模型在体外通过氧和葡萄糖剥夺（OGD）和在体内通过改良版本的Rice-Vannucci HI模型在10日龄大鼠幼崽。EPO处理的细胞暴露于AG 490（JAK-2或TIMP-1中和抗体的抑制剂）2小时，伴随OGD。检测细胞死亡率、JAK-2和信号转导与转录激活蛋白-3（STAT-3）磷酸化水平、TIMP-1表达和基质金属蛋白酶-9（MMP-9）活性，并与常氧组进行比较。在HI后1小时对低血糖缺血动物进行治疗，并在48小时后进行评价。我们的数据表明，EPO显着增加细胞存活率，与增加TIMP-1活性，磷酸化JAK-2，STAT-3，并降低MMP-9活性在体内和体外。在两种模型中，EPO的保护作用通过抑制JAK-2或TIMP-1而逆转。结论：JAK-2、STAT-3和TIMP-1是EPO诱导的缺氧缺血性神经保护作用的关键介质。
Previous studies have shown that erythropoietin (EPO) is neuroprotective in both in vivo and in vitro models of hypoxia ischemia. However theses studies hold limited clinical translations because the underlying mechanism remains unclear and the key molecules involved in EPO-induced neuroprotection are still to be determined. This study investigated if tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and if its upstream regulator signaling molecule Janus kinase-2 (JAK-2) are critical in EPO-induced neuroprotection. Hypoxia Ischemia (HI) was modeled in-vitro by oxygen and glucose deprivation (OGD) and in-vivo by a modified version of Rice-Vannucci model of HI in 10-day-old rat pups. EPO treated cells were exposed to AG490, an inhibitor of JAK-2 or TIMP-1 neutralizing antibody for 2 hours with OGD. Cell death, phosphorylation of JAK-2 and signal transducers and activators of transcription protein-3 (STAT-3), TIMP-1 expression, and matrix metalloproteinase-9 (MMP-9) activity were measured and compared with normoxic group. Hypoxic ischemic animals were treated one hour following HI and evaluated 48 hours after. Our data showed that EPO significantly increased cell survival, associated with increased TIMP-1 activity, phosphorylation of JAK-2, STAT-3, and decreased MMP-9 activity in vivo and in vitro. EPO’s protective effects were reversed by inhibition of JAK-2 or TIMP-1 in both models. We concluded that JAK-2, STAT-3 and TIMP-1 are key mediators of EPO-induced neuroprotection during hypoxia ischemia injury.
登录
查看更多内容
影响因子：
7.8
作者：
Ihle, J N
通讯作者：
Ihle, J N
DOI：
10.1136/mp.54.5.289
发表时间：
2001-10-01
期刊：
JOURNAL OF CLINICAL PATHOLOGY-MOLECULAR PATHOLOGY
影响因子：
--
作者：
Isaksen, B;Fagerhol, MK
通讯作者：
Fagerhol, MK
影响因子：
5.5
作者：
Agani, FH;Puchowicz, M;LaManna, J
通讯作者：
LaManna, J
影响因子：
2.9
作者：
Calvert, JW;Yin, W;Zhang, JH
通讯作者：
Zhang, JH
影响因子：
5.6
作者：
Andrian, Elisoa;Mostefaoui, Yakout;Grenier, Daniel
通讯作者：
Grenier, Daniel