巨噬细胞移动抑制因子增强心脏抗缺血能力

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Stress modulator could help combat cardiac ischemic response

31 January 2008

MedWire News: Scientists report that a cytokine - the macrophage migration inhibitory factor (MIF) - influences the heart's ability to deal with ischemia.

They demonstrate that under hypoxic conditions MIF activates the cellular stress response enzyme AMP-activated protein kinase (AMPK), which in turn is a key regulator of metabolism protecting against ischemic damage.

\"We found that when MIF is released in response to a lack of oxygen, it causes the activation of AMPK,\" co-author Richard Bucala, from Yale University in Connecticut, USA, expanded. \"Thus, this protein which contributes to inflammatory diseases has a protective metabolic effect in the heart.\"

Writing in the journal Nature, Bucala and colleagues explain that AMPK is a known regulator of glucose uptake during cellular stress. AMPK senses the cellular energy state and sets various pathways in motion to increase cellular ATP production and limit energy consumption when oxygen is scarce.

In searching for a modulator of AMPK in the heart, the researchers focused on its potential interaction with MIF - a cytokine that controls the inflammatory \"set point\" by regulating the release of other pro-inflammatory cytokines and is involved in the pathogenesis of certain inflammatory diseases. MIF also stimulates glycolysis and increases cellular glucose uptake, the authors note.

The team found that inducing ischemia in isolated murine hearts triggered MIF release, leading to AMPK activation and impaired downstream glucose uptake.

They then showed that mice lacking the MIF gene had an impaired cardiac ischemic AMPK signaling response and suffered greater cardiac damage in response to ischemia-reperfusion, in particular a 2.3-fold greater infarct size, compared with wild-type mice.

Further analysis showed that a common polymorphism in the MIF promoter affected MIF release in cultured human fibroblasts, and consequently AMPK activation in response to hypoxic conditions. This could be ameliorated by addition of exogenous MIF.

The authors say these findings \"raise the possibility that a common polymorphism in the MIF promoter influences the susceptibility of patients with coronary artery disease to ischemic injury.\"

Put more simply, senior author Lawrence Young, also of Yale University, explained: \"We might be able to identify individuals, based on their genetic characteristics, who are likely to suffer more cardiac damage during a heart attack.\"

Noting that AMPK is already under investigation as a potential therapeutic target in ischemic heart disease, the authors write: \"Treatment with MIF or MIF agonists warrants further study as an adjunctive therapy targeted at AMPK activation during acute myocardial ischemia or infarction.\"

Nature 2008; 358: 464-474
MedWire新闻：科学家报道，巨噬细胞移动抑制因子(MIF)影响心脏抗缺血能力。他们证实，在缺氧环境下MIF激活细胞内应激反应酶－腺苷酸活化蛋白激酶（AMPK），它是随后抗缺血损伤代谢调控的重要元素。“我们发现，当MIF缺氧反应性释放时，它导致AMPK活化，”合著者Richard Bucala补充，他来自美国康涅狄格州耶鲁大学。“因而，这个炎性疾病相关蛋白，在心脏呈现了保护性代谢效应。”Bucala及同事在《Nature》杂志如是说明：AMPK是在细胞应激过程中葡萄糖摄取的已知调节因子；AMPK感知细胞内能态，启动多种途径增加细胞内ATP生成，并限制能量消耗当缺氧时。在寻找AMPK心脏调节因子的过程中，研究者注意到其与MIF的潜在相互作用。细胞因子MIF通过调节其它致炎(炎症前)细胞因子释放控制炎症反应“调定点”，参与某些炎性疾病的发病。研究小组发现，诱导离体鼠心肌缺血触发了MIF的释放，导致AMPK活化＆下游葡萄糖摄取受损。他们接着说明，缺乏MIF基因的小鼠，心肌缺血反应性AMPK信号通路受损，缺血再灌注性心肌损伤更严重，值得注意的是和野生型小鼠比较梗死面积增加了2.3倍（2.3-fold greater ，是增加了2.3倍还是增加到2.3倍？）。进一步的分析显示，MIF基因启动子区一常见的多态性影响体外培养的人成纤维细胞MIF释放，从而AMPK缺氧反应性活化。这个可以通过加入外源性MIF得到改善。作者说这些发现“增加了MIF基因启动子区这一常见多态影响冠心病患者缺血损伤易感性的可能”。说得更简单点，通讯作者Lawrence Young（耶鲁大学）解释：“一些人在心脏病发作的过程中心肌损伤更严重，基于他们的遗传特点，我们也许可以个体化每个人。”注意，AMPK作为缺血性心脏病的潜在治疗靶点已经开始研究，作者写道：“针对急性心肌缺血或梗死进程中AMPK活化调节，MIF或MIF激动剂作为辅助治疗手段的进一步研究很有希望。”

Nature 2008; 358: 464-474
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