Uncovering a new role for peroxidase enzymes as drivers of angiogenesis

Vasilios (Bill) Panagopoulos, Irene Zinonos, Damien A. Leach, Shelley J. Hay, Vasilios Liapis, Aneta Zysk, Wendy V. Ingman, Mark O. DeNichilo, Andreas Evdokiou

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

LanguageEnglish
Pages128-138
Number of pages11
JournalInternational Journal of Biochemistry and Cell Biology
Volume68
DOIs
Publication statusPublished - 1 Nov 2015

Keywords

  • Angiogenesis
  • Eosinophil peroxidase
  • Inflammation
  • Myeloperoxidase

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

Cite this

Panagopoulos, Vasilios (Bill) ; Zinonos, Irene ; Leach, Damien A. ; Hay, Shelley J. ; Liapis, Vasilios ; Zysk, Aneta ; Ingman, Wendy V. ; DeNichilo, Mark O. ; Evdokiou, Andreas. / Uncovering a new role for peroxidase enzymes as drivers of angiogenesis. In: International Journal of Biochemistry and Cell Biology. 2015 ; Vol. 68. pp. 128-138.
@article{7a441c6b7eae443497a4f36cb12af8cb,
title = "Uncovering a new role for peroxidase enzymes as drivers of angiogenesis",
abstract = "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.",
keywords = "Angiogenesis, Eosinophil peroxidase, Inflammation, Myeloperoxidase",
author = "Panagopoulos, {Vasilios (Bill)} and Irene Zinonos and Leach, {Damien A.} and Hay, {Shelley J.} and Vasilios Liapis and Aneta Zysk and Ingman, {Wendy V.} and DeNichilo, {Mark O.} and Andreas Evdokiou",
year = "2015",
month = "11",
day = "1",
doi = "10.1016/j.biocel.2015.09.006",
language = "English",
volume = "68",
pages = "128--138",
journal = "International Journal of Biochemistry and Cell Biology",
issn = "1357-2725",
publisher = "Elsevier Limited",

}

Panagopoulos, VB, Zinonos, I, Leach, DA, Hay, SJ, Liapis, V, Zysk, A, Ingman, WV, DeNichilo, MO & Evdokiou, A 2015, 'Uncovering a new role for peroxidase enzymes as drivers of angiogenesis', International Journal of Biochemistry and Cell Biology, vol. 68, pp. 128-138. https://doi.org/10.1016/j.biocel.2015.09.006

Uncovering a new role for peroxidase enzymes as drivers of angiogenesis. / Panagopoulos, Vasilios (Bill); Zinonos, Irene; Leach, Damien A.; Hay, Shelley J.; Liapis, Vasilios; Zysk, Aneta; Ingman, Wendy V.; DeNichilo, Mark O.; Evdokiou, Andreas.

In: International Journal of Biochemistry and Cell Biology, Vol. 68, 01.11.2015, p. 128-138.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Uncovering a new role for peroxidase enzymes as drivers of angiogenesis

AU - Panagopoulos, Vasilios (Bill)

AU - Zinonos, Irene

AU - Leach, Damien A.

AU - Hay, Shelley J.

AU - Liapis, Vasilios

AU - Zysk, Aneta

AU - Ingman, Wendy V.

AU - DeNichilo, Mark O.

AU - Evdokiou, Andreas

PY - 2015/11/1

Y1 - 2015/11/1

N2 - 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.

AB - 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.

KW - Angiogenesis

KW - Eosinophil peroxidase

KW - Inflammation

KW - Myeloperoxidase

UR - http://www.scopus.com/inward/record.url?scp=84943248400&partnerID=8YFLogxK

U2 - 10.1016/j.biocel.2015.09.006

DO - 10.1016/j.biocel.2015.09.006

M3 - Article

VL - 68

SP - 128

EP - 138

JO - International Journal of Biochemistry and Cell Biology

T2 - International Journal of Biochemistry and Cell Biology

JF - International Journal of Biochemistry and Cell Biology

SN - 1357-2725

ER -