Uncovering a new role for peroxidase enzymes as drivers of angiogenesis

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...

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Bibliographic Details
Published in:The international journal of biochemistry & cell biology 2015-11, Vol.68, p.128-138
Main Authors: Panagopoulos, Vasilios, Zinonos, Irene, Leach, Damien A., Hay, Shelley J., Liapis, Vasilios, Zysk, Aneta, Ingman, Wendy V., DeNichilo, Mark O., Evdokiou, Andreas
Format: Article
Language:English
Subjects:
Angiogenesis
Aniline Compounds - pharmacology
Animals
Basic Helix-Loop-Helix Transcription Factors - genetics
Basic Helix-Loop-Helix Transcription Factors - metabolism
Biological Assay
Cell Movement - drug effects
Cell Proliferation - drug effects
Collagen - chemistry
Drug Combinations
Endocytosis - drug effects
Enzyme Inhibitors - pharmacology
Eosinophil peroxidase
Eosinophil Peroxidase - antagonists & inhibitors
Eosinophil Peroxidase - genetics
Eosinophil Peroxidase - metabolism
Eosinophil Peroxidase - pharmacology
Female
Focal Adhesion Kinase 1 - genetics
Focal Adhesion Kinase 1 - metabolism
Gene Expression Regulation
Human Umbilical Vein Endothelial Cells - cytology
Human Umbilical Vein Endothelial Cells - drug effects
Human Umbilical Vein Endothelial Cells - metabolism
Humans
Inflammation
Laminin - chemistry
Mice
Mice, Inbred BALB C
Mitogen-Activated Protein Kinase 1 - genetics
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3 - genetics
Mitogen-Activated Protein Kinase 3 - metabolism
Myeloperoxidase
Neovascularization, Physiologic - drug effects
p38 Mitogen-Activated Protein Kinases - genetics
p38 Mitogen-Activated Protein Kinases - metabolism
Peroxidase - antagonists & inhibitors
Peroxidase - genetics
Peroxidase - metabolism
Peroxidase - pharmacology
Proteoglycans - chemistry
Proto-Oncogene Proteins c-akt - genetics
Proto-Oncogene Proteins c-akt - metabolism
Signal Transduction
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Summary: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 both in vitro and in 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.
ISSN:1357-2725
1878-5875
DOI:10.1016/j.biocel.2015.09.006