Myeloid-related protein-8/14 is critical for the biological response to vascular injury.
Myeloid-related protein-8/14 is critical for the biological response to vascular injury.
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DOI：
10.1161/circulationaha.108.814582
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发表时间：
2009-08-04
期刊：
影响因子：
37.8
通讯作者：
Simon DI
中科院分区：
文献类型：
--
作者：
Croce K;Gao H;Wang Y;Mooroka T;Sakuma M;Shi C;Sukhova GK;Packard RR;Hogg N;Libby P;Simon DI
MRP-8 （S100A8）和MRP-14 （S100A9）是s100钙调节蛋白家族的成员，通过激活toll样受体-4和RAGE来调节髓细胞功能和控制炎症。急性冠状动脉综合征患者的转录谱分析方法确定MRP-14为心肌梗死的新预测因子。进一步的研究表明，血浆MRP-8/14异源二聚体水平升高预示着首次和复发心血管事件的风险增加。除了作为风险标志物，MRP-8/14是否直接参与动脉炎症和疾病尚不清楚。我们评估了野生型（WT）和MRP-14缺陷（MRP-14−/−）小鼠的血管炎症，这些小鼠缺乏MRP-8/14复合物，伴有实验性动脉损伤、血管炎或动脉粥样硬化。股动脉丝损伤后，与WT小鼠相比，MRP-14 - / -小鼠的白细胞积累、细胞增殖和新生内膜形成显著减少。在细胞因子诱导的局部施瓦茨曼样反应中产生血栓出血性血管炎，MRP-14 - / -小鼠的中性粒细胞积累、病变严重程度和出血面积显著减少。在高脂肪喂养下，与单独缺乏ApoE的小鼠相比，ApoE和MRP-8/14复合物双重缺乏的小鼠在动脉粥样硬化病变区域和斑块中巨噬细胞积聚的减少。本研究表明，MRP-8/14广泛调节血管炎症，并通过促进白细胞募集参与血管损伤的生物学反应。
MRP-8 (S100A8) and MRP-14 (S100A9) are members of the S100-family of calcium-modulated proteins that regulate myeloid cell function and control inflammation, in part, through activation of toll-like receptor-4 and RAGE. A transcriptional profiling approach in patients with acute coronary syndromes identified MRP-14 as a novel predictor of myocardial infarction. Further studies demonstrated that elevated plasma levels of MRP-8/14 heterodimer predict increased risk of first and recurrent cardiovascular events. Beyond its serving as a risk marker, whether MRP-8/14 participates directly in arterial inflammation and disease remains unclear. We evaluated vascular inflammation in wild-type (WT) and MRP-14-deficient (MRP-14−/−) mice that lack MRP-8/14 complexes with experimental arterial injury, vasculitis, or atherosclerosis. After femoral artery wire injury, MRP-14−/− mice had significant reductions in leukocyte accumulation, cellular proliferation, and neointima formation compared to WT mice. In a cytokine-induced local Schwartzman-like reaction that produces thrombohemorrhagic vasculitis, MRP-14−/− mice had significant reductions in neutrophils accumulation, lesion severity and hemorrhagic area. In response to high-fat feeding, mice doubly deficient in ApoE and MRP-8/14 complexes had attenuation in atherosclerotic lesion area and in macrophage accumulation in plaques compared to mice deficient in ApoE alone. This study demonstrates that MRP-8/14 broadly regulates vascular inflammation and contributes to the biological response to vascular injury by promoting leukocyte recruitment.