The potentiation of myeloperoxidase activity by the glycosaminoglycan-dependent binding of myeloperoxidase to proteins of the extracellular matrix
The potentiation of myeloperoxidase activity by the glycosaminoglycan-dependent binding of myeloperoxidase to proteins of the extracellular matrix
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DOI：
10.1016/j.bbagen.2013.05.024
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发表时间：
2013-10-01
影响因子：
3
通讯作者：
Eiserich, Jason P.
中科院分区：
文献类型：
--
作者：
Kubala, Lukas;Kolarova, Hana;Eiserich, Jason P.
背景：髓过氧化物酶（MPO）是一种丰富的由中性粒细胞表达的血红蛋白，在血管疾病的发生中起重要作用。在循环中性粒细胞脱粒后，MPO以静电依赖的方式与内皮细胞表面结合，并经历胞外迁移到潜在的细胞外基质（ECM）。然而，调控MPO与内皮下ECM蛋白结合的机制，以及这种结合是否调节其酶功能尚不清楚。方法：我们研究了MPO与来自主动脉内皮细胞、主动脉平滑肌细胞和成纤维细胞的ECM的结合，纯化的ECM蛋白，以及糖胺聚糖对这些关联的调节。测试了MPO与ECM蛋白结合后的氧化和氯化电位。结果：MPO与ECM蛋白IV型胶原蛋白和纤维连接蛋白结合，并且这种结合通过将这些蛋白与糖胺聚糖预先孵育而增强。相应地，孵育期间溶液中过量的糖胺聚糖会抑制MPO与IV型胶原和纤维连接蛋白的结合。细胞来源的ECM证实了这些观察结果。MPO与IV型胶原和纤维连接蛋白结合后，保留了氧化和氯化电位；甚至MPO活性在IV型胶原和纤维连接蛋白存在下也有增强。结论：总的来说，这些数据表明MPO通过静电相互作用与ECM蛋白结合，MPO的氯化和氧化活性在与这些蛋白结合后得到增强。一般意义：我们的发现为MPO与ECM蛋白相互作用的分子机制提供了新的见解。(c) 2013 Elsevier B.V.版权所有
Background: Myeloperoxidase (MPO) is an abundant hemoprotein expressed by neutrophil granulocytes that is recognized to play an important role in the development of vascular diseases. Upon degranulation from circulating neutrophil granulocytes, MPO binds to the surface of endothelial cells in an electrostatic-dependent manner and undergoes transcytotic migration to the underlying extracellular matrix (ECM). However, the mechanisms governing the binding of MPO to subendothelial ECM proteins, and whether this binding modulates its enzymatic functions are not well understood.Methods: We investigated MPO binding to ECM derived from aortic endothelial cells, aortic smooth muscle cells, and fibroblasts, and to purified ECM proteins, and the modulation of these associations by glycosaminoglycans. The oxidizing and chlorinating potential of MPO upon binding to ECM proteins was tested.Results: MPO binds to the ECM proteins collagen IV and fibronectin, and this association is enhanced by the pre-incubation of these proteins with glycosaminoglycans. Correspondingly, an excess of glycosaminoglycans in solution during incubation inhibits the binding of MPO to collagen IV and fibronectin. These observations were confirmed with cell-derived ECM. The oxidizing and chlorinating potential of MPO was preserved upon binding to collagen IV and fibronectin; even the potentiation of MPO activity in the presence of collagen IV and fibronectin was observed.Conclusions: Collectively, the data reveal that MPO binds to ECM proteins on the basis of electrostatic interactions, and MPO chlorinating and oxidizing activity is potentiated upon association with these proteins.General significance: Our findings provide new insights into the molecular mechanisms underlying the interaction of MPO with ECM proteins. (c) 2013 Elsevier B.V. All rights reserved.