Angiogenic activity of bFGF and VEGF suppressed by proteolytic cleavage by neutrophil elastase.
Neutrophil elastase (NE), a serine protease released from the azurophil granules of activated neutrophil, proteolytically cleaves multiple cytokines, and cell surface proteins. In the present study, we examined whether NE affects the biological abilities of angiogenic growth factors such as basic-fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). NE degraded bFGF and VEGF in a time- and concentration-dependent manner, and these degradations were suppressed by sivelestat, a synthetic inhibitor of NE. The bFGF- or VEGF-mediated proliferative activity of human umbilical vein endothelial cells was inhibited by NE, and the activity was recovered by sivelestat. Furthermore, NE reduced the bFGF- or VEGF-induced tubulogenic response of the mice aortas, ex vivo angiogenesis assay, and these effects were also recovered by sivelestat. Neutrophil-derived NE degraded potent angiogenic factors, resulting in loss of their angiogenic activity. These findings provide additional insight into the role played by neutrophils in the angiogenesis process at sites of inflammation.
Ai
Shingo
S
Department of Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Cheng
Xian Wu
XW
Inoue
Aiko
A
Nakamura
Kae
K
Okumura
Kenji
K
Iguchi
Akihisa
A
Murohara
Toyoaki
T
Kuzuya
Masafumi
M
D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology / Q000502:physiology*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D018919:Neovascularization, Physiologic; D013449:Sulfonamides / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology / Q000502:physiology*
D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; C069195:sivelestat; D019272:Leukocyte Elastase; D005998:Glycine