Urocortin protects against ischemic and reperfusion injury via a MAPK-dependent pathway
Urocortin protects against ischemic and reperfusion injury via a MAPK-dependent pathway
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DOI：
10.1074/jbc.275.12.8508
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发表时间：
2000-03-24
影响因子：
4.8
通讯作者：
Latchman, DS
中科院分区：
文献类型：
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作者：
Brar, BK;Jonassen, AK;Latchman, DS
尿皮质素 (UCN) 是一种与下丘脑促肾上腺皮质激素释放激素相关的肽，与心脏中表达的促肾上腺皮质激素释放激素受体 2 β 具有高亲和力。在这项研究中，我们报告说，在模拟缺氧/缺血之前和模拟缺氧/缺血后复氧时，对原代心肌细胞培养物施用 UCN 可以防止细胞死亡。 UCN 介导的细胞存活通过台盼蓝排除、DNA 3'-OH 末端标记 (TUNEL)、膜联蛋白 V 和荧光激活细胞分选来测量。为了探索造成这种效应的机制，我们研究了 MAPK 依赖性途径的参与。 UCN 引起 ERK1/2-p42/44 快速磷酸化，而阻断 MEK1-ERK1/2-p42/44 级联的 PD98059 也抑制 UCN 的生存促进作用。最重要的是，UCN 减少了离体大鼠离体心脏局部缺血/再灌注的损伤，在缺血前或缺血后再灌注时给予 UCN 时观察到保护作用。这表明 UCN 作为心脏保护剂的一种新功能，可以在缺血后再灌注时发挥作用。
Urocortin (UCN) is a peptide related to hypothalamic corticotrophin-releasing hormone and binds with high affinity to corticotrophin-releasing hormone receptor-2 beta, which is expressed in the heart. In this study, we report that UCN prevented cell death when administered to primary cardiac myocyte cultures both prior to simulated hypoxia/ischemia and at the point of reoxygenation after simulated hypoxia/ischemia. UCN-mediated cell survival was measured by trypan blue exclusion, 3'-OH end labeling of DNA (TUNEL), annexin V, and fluorescence-activated cell sorting. To explore the mechanisms that could be responsible for this effect, we investigated the involvement of MAPK-dependent pathways. UCN caused rapid phosphorylation of ERK1/2-p42/44, and PD98059, which blocks the MEK1-ERK1/2-p42/44 cascade, also inhibited the survival-promoting effect of UCN. Most important, UCN reduced damage in isolated rat hearts ex vivo subjected to regional ischemia/reperfusion, with the protective effect being observed when UCN was given either prior to ischemia or at the time of reperfusion after ischemia. This suggests a novel function of UCN as a cardioprotective agent that could act when given after ischemia, at reperfusion.