Uncovering a new role for peroxidase enzymes as drivers of angiogenesis.
Uncovering a new role for peroxidase enzymes as drivers of angiogenesis.
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DOI：
10.1016/j.biocel.2015.09.006
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发表时间：
2015-11
期刊：
影响因子：
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通讯作者：
V. Panagopoulos;Irene Zinonos;D. Leach;S. Hay;Vasilios Liapis;A. Zysk;W. Ingman;M. DeNichilo;A. Evdokiou
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文献类型：
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作者：
V. Panagopoulos;Irene Zinonos;D. Leach;S. Hay;Vasilios Liapis;A. Zysk;W. Ingman;M. DeNichilo;A. Evdokiou
过氧化物酶是由激活的免疫细胞在炎症部位释放的含血红素的酶。迄今为止，它们在人类健康中的功能性作用主要限于提供一种对抗入侵细菌和其他病原微生物的氧化防御机制。我们的实验室最近确定了过氧化物酶在刺激成纤维细胞迁移和胶原蛋白生物合成中的新功能作用，为炎症与介导组织修复和再生的促纤维化事件之间的因果关系提供了新的见解。过氧化物酶在血管内和血管附近的水平升高，但从未报道过它们直接参与血管生成。本文首次报道髓过氧化物酶（MPO）和嗜酸性粒细胞过氧化物酶（EPO）可被人脐静脉内皮细胞（HUVEC）内化，促进细胞增殖、迁移、侵袭，并在体外和体内刺激血管生成。使用特异性过氧化物酶抑制剂4-ABAH减弱这些促血管生成作用，表明酶的催化活性在介导这种反应中是必不可少的。从机制上讲，我们提供了证据表明MPO和EPO调节内皮FAK、Akt、p38 MAPK、ERK 1/2磷酸化和HIF-2α的稳定，最终在关键血管生成途径的转录调节中达到顶峰。这些发现首次揭示了过氧化物酶作为血管生成驱动因子的重要和先前未被怀疑的作用，并提示过氧化物酶抑制剂可能具有治疗炎症驱动的血管生成相关疾病的治疗潜力。
Peroxidases are heme-containing enzymes released by activated immune cells at sites of inflammation. To-date their functional role in human health has mainly been limited to providing a mechanism for oxidative defence against invading bacteria and other pathogenic microorganisms. Our laboratory has recently identified a new functional role for peroxidase enzymes in stimulating fibroblast migration and collagen biosynthesis, offering a new insight into the causative association between inflammation and the pro-fibrogenic events that mediate tissue repair and regeneration. Peroxidases are found at elevated levels within and near blood vessels however, their direct involvement in angiogenesis has never been reported. Here we report for the first time that myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are readily internalised by human umbilical vein endothelial cells (HUVEC) where they promote cellular proliferation, migration, invasion, and stimulate angiogenesis bothin vitroandin vivo. These pro-angiogenic effects were attenuated using the specific peroxidase inhibitor 4-ABAH, indicating the enzyme's catalytic activity is essential in mediating this response. Mechanistically, we provide evidence that MPO and EPO regulate endothelial FAK, Akt, p38 MAPK, ERK1/2 phosphorylation and stabilisation of HIF-2α, culminating in transcriptional regulation of key angiogenesis pathways.These findings uncover for the first time an important and previously unsuspected role for peroxidases as drivers of angiogenesis, and suggest that peroxidase inhibitors may have therapeutic potential for the treatment of angiogenesis related diseases driven by inflammation.