Cardioprotection Through S-Nitros(yl)ation of Macrophage Migration Inhibitory Factor
Cardioprotection Through S-Nitros(yl)ation of Macrophage Migration Inhibitory Factor
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DOI：
10.1161/circulationaha.111.069104
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发表时间：
2012-04-17
期刊：
影响因子：
37.8
通讯作者：
Rassaf, Tienush
中科院分区：
文献类型：
--
作者：
Luedike, Peter;Hendgen-Cotta, Ulrike B.;Rassaf, Tienush
背景-巨噬细胞移动抑制因子（MIF）是一种结构独特的炎症细胞因子，通过细胞内外过程控制人体生理和疾病的细胞信号。巨噬细胞移动抑制因子已被证明介导疾病恶化和有益的效果，但控制这些不同的功能的基本机制（S）知之甚少。方法和结果-在这里，我们已经确定了一个S-硝基（yl）化修饰的MIF，调节心肌再灌注损伤的保护功能表型的MIF。巨噬细胞移动抑制因子含有3个半胱氨酸（Cys）残基;使用重组wtMIF和位点特异性MIF突变体，我们已经确定Cys-81被S-硝基（yl）化修饰，而CXXC衍生的Cys残基的MIF保持不受影响。在Cys-81处的选择性S-亚硝基硫醇形成导致MIF的氧化还原酶活性加倍。重要的是，S-亚硝基硫醇-MIF的形成在体外和体内都进行了测量，并导致再灌注心脏中心肌细胞凋亡的减少。这种减少是由一个S-亚硝基硫醇-MIF，但不是Cys 81丝氨酸（Ser）-MIF murides依赖性的减少心肌缺血/再灌注injuries.Conclusions-S-nitros（yl）化的MIF是一个关键的新的监管机制，提供增强的活动，从而增加心肌再灌注损伤的细胞保护作用的梗死面积在体内模型。（循环。2012; 125：1880-1889.）
Background-Macrophage migration inhibitory factor (MIF) is a structurally unique inflammatory cytokine that controls cellular signaling in human physiology and disease through extra-and intracellular processes. Macrophage migration inhibitory factor has been shown to mediate both disease-exacerbating and beneficial effects, but the underlying mechanism(s) controlling these diverse functions are poorly understood.Methods and Results-Here, we have identified an S-nitros(yl)ation modification of MIF that regulates the protective functional phenotype of MIF in myocardial reperfusion injury. Macrophage migration inhibitory factor contains 3 cysteine (Cys) residues; using recombinant wtMIF and site-specific MIF mutants, we have identified that Cys-81 is modified by S-nitros(yl) ation whereas the CXXC-derived Cys residues of MIF remained unaffected. The selective S-nitrosothiol formation at Cys-81 led to a doubling of the oxidoreductase activity of MIF. Importantly, S-nitrosothiol-MIF formation was measured both in vitro and in vivo and led to a decrease in cardiomyocyte apoptosis in the reperfused heart. This decrease was paralleled by a S-nitrosothiol-MIF-but not Cys81 serine (Ser)-MIF mutant-dependent reduction of infarct size in an in vivo model of myocardial ischemia/reperfusion injury.Conclusions-S-nitros(yl)ation of MIF is a pivotal novel regulatory mechanism, providing enhanced activity resulting in increased cytoprotection in myocardial reperfusion injury. (Circulation. 2012; 125: 1880-1889.)