Cardiac macrophage migration inhibitory factor inhibits JNK pathway activation and injury during ischemia/reperfusion
Cardiac macrophage migration inhibitory factor inhibits JNK pathway activation and injury during ischemia/reperfusion
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DOI：
10.1172/jci39738
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发表时间：
2009-12-01
影响因子：
15.9
通讯作者：
Young, Lawrence H.
中科院分区：
文献类型：
--
作者：
Qi, Dake;Hu, Xiaoyue;Young, Lawrence H.
巨噬细胞迁移抑制因子（Macrophage migration inhibitory factor， MIF）是一种促炎细胞因子，也可调节生理性细胞信号通路。MIF在心肌细胞中表达，并通过增强缺血时AMPK的活性来限制心脏损伤。再灌注损伤在一定程度上是由应激激酶JNK的激活介导的，但MIF是否在这种情况下调节JNK尚不清楚。我们研究了MIF在小鼠心脏实验性缺血/再灌注过程中调控JNK激活和心脏损伤中的作用。离体灌注的Mif（-/-）心脏在缺血/再灌注后比WT心脏有更大的收缩功能障碍、坏死和JNK激活，上游MAPK激酶4磷酸化增加。如果在再灌注期间存在重组MIF，这些作用被逆转，表明再灌注期间MIF缺乏加剧了损伤。激活的JNK通过调节bcl2相关的细胞死亡激动剂（BAD）磷酸化以促进细胞凋亡的方式起作用，这种作用在缺血/再灌注后的Mif（-/-）心脏中得到加强。在MIF（-/-）小鼠冠状动脉闭塞和再灌注后，体内观察到MIF缺乏的类似有害影响。重要的是，在低氧再氧化后，在启动子活性最低的MIF等位基因纯合的人成纤维细胞中也观察到过量的JNK激活。这些数据表明，内源性MIF在再灌注过程中抑制JNK通路的激活，保护心脏免受损伤。这些发现对低表达MIF等位基因患者具有临床意义。
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that also modulates physiologic cell signaling pathways. MIF is expressed in cardiomyocytes and limits cardiac injury by enhancing AMPK activity during ischemia. Reperfusion injury is mediated in part by activation of the stress kinase JNK, but whether MIF modulates JNK in this setting is unknown. We examined the role of MIF in regulating JNK activation and cardiac injury during experimental ischemia/reperfusion in mouse hearts. Isolated perfused Mif(-/-) hearts had greater contractile dysfunction, necrosis, and JNK activation than WT hearts, with increased upstream MAPK kinase 4 phosphorylation, following ischemia/reperfusion. These effects were reversed if recombinant MIF was present during reperfusion, indicating that MIF deficiency during reperfusion exacerbated injury. Activated JNK acts in a proapoptotic manner by regulating BCL2-associated agonist of cell death (BAD) phosphorylation, and this effect was accentuated in Mif(-/-) hearts after ischemia/reperfusion. Similar detrimental effects of MIF deficiency were observed in vivo following coronary occlusion and reperfusion in Mif(-/-) mice. Importantly, excess JNK activation also was observed after hypoxia-reoxygenation in human fibroblasts homozygous for the MIF allele with the lowest level of promoter activity. These data indicate that endogenous MIF inhibits JNK pathway activation during reperfusion and protects the heart from injury. These findings have clinical implications for patients with the low-expression MIF allele.