Erythropoietin prevents the acute myocardial inflammatory response induced by ischemia/reperfusion via induction of AP-1
Erythropoietin prevents the acute myocardial inflammatory response induced by ischemia/reperfusion via induction of AP-1
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DOI：
10.1016/j.cardiores.2004.11.019
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发表时间：
2005-02-15
影响因子：
10.8
通讯作者：
Kvietys, PR
中科院分区：
文献类型：
--
作者：
Rui, T;Feng, QP;Kvietys, PR
目的：促红细胞生成素（EPO）对缺血再灌注（I/R）所致心肌功能障碍的保护作用。由于I/R诱导的心肌功能障碍与急性炎症反应，我们评估了EPO的抗炎特性，在体外和体内模型的I/R。方法：分离的心肌细胞暴露于缺氧/复氧（A/R;在体外对应I/R）。结果：在体外，A/R增加了心肌细胞的氧化应激，并将心肌细胞转化为促炎表型（这些心肌细胞诱导PMN跨内皮迁移）。用EPO预处理心肌细胞可防止A/R诱导的促炎作用。EPO增加心肌细胞（1）AP-1（c-fos/c-jun）的核转位，（2）eNOS蛋白表达，但不增加iNOS蛋白表达，（3）NO产生。AP-1“诱饵”寡核苷酸阻止EPO诱导eNOS并逆转EPO的有益作用。磷脂酰肌醇3（P13）-激酶抑制剂阻止EPO诱导的AP-1核转位。在体内，在野生型小鼠中，I/R诱导心肌MPO活性增加（指示PMN浸润）; EPO预处理小鼠可防止这种效应。EPO的这种抗炎作用在心脏特异性c-fos（-/-）小鼠中没有观察到。结论：总的来说，这些发现表明EPO可以改善I/R的体外和体内模型中的心肌炎症反应。EPO的这种有益作用是由eNOS衍生的NO通过AP-1的P13激酶依赖性激活介导的。(C)2004年欧洲心脏病学会。Elsevier B. V.出版，保留所有权利。
Objective: Erythropoietin (EPO) prevents the myocardial dysfunction induced by ischemia/reperfusion (I/R). Since I/R-induced myocardial dysfunction is associated with an acute inflammatory response, we assessed the anti-inflammatory properties of EPO using in vitro and in vivo models of I/R.Methods: Isolated cardiac myocytes were exposed to anoxia/reoxygenation (A/R; the in vitro counterpart to I/R). Hearts were challenged with I/R in situ.Results: In vitro, A/R increased myocyte oxidant stress and converted the myocytes to a proinflammatory phenotype (these myocytes induced PMN transendothelial migration). pretreatment of the myocytes with EPO prevented the A/R-induced proinflammatory effects. EPO increased myocyte (1) nuclear translocation of AP-1 (c-fos/c-jun), (2) eNOS, but not iNOS, protein expression, and (3) NO production. An AP-1 "decoy" oligonucleotide prevented the induction of eNOS by EPO and reversed the beneficial effect of EPO. An inhibitor of phosphatidylinostol 3 (P13)-kinase prevented the nuclear translocation of AP-1 induced by EPO. In vivo, in wild type mice, I/R induced an increase in myocardial MPO activity (indicative of PMN infiltration); an effect prevented by pretreatment of the mice with EPO. This anti-inflammatory effect of EPO was not observed in cardiac specific c-fos(-/-) mice.Conclusions: Collectively, these findings indicate that EPO can ameliorate the myocardial inflammatory response in both in vitro and in vivo models of I/R. This beneficial effect of EPO is mediated by eNOS-derived NO via a P13-kinase-dependent activation of AP-1. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.