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Heparin-binding protein targeted to mitochondrial compartments protects endothelial cells from apoptosis

Olofsson, A M LU ; Vestberg, M LU ; Herwald, H LU orcid ; Rygaard, J ; David, G ; Arfors, K E ; Linde, V ; Flodgaard, H ; Dedio, J and Müller-Esterl, W , et al. (1999) In Journal of Clinical Investigation 104(7). p.885-894
Abstract

Neutrophil-borne heparin-binding protein (HBP) is a multifunctional protein involved in the progression of inflammation. HBP is stored in neutrophil granules and released upon stimulation of the cells in proximity to endothelial cells. HBP affects endothelial cells in multiple ways; however, the molecular and cellular mechanisms underlying the interaction of HBP with these cells are unknown. Affinity isolation and enzymatic degradation demonstrated that HBP released from human neutrophils binds to endothelial cell-surface proteoglycans, such as syndecans and glypican. Flow cytometry indicated that a significant fraction of proteoglycan-bound HBP is taken up by the endothelial cells, and we used radiolabeled HBP to determine the... (More)

Neutrophil-borne heparin-binding protein (HBP) is a multifunctional protein involved in the progression of inflammation. HBP is stored in neutrophil granules and released upon stimulation of the cells in proximity to endothelial cells. HBP affects endothelial cells in multiple ways; however, the molecular and cellular mechanisms underlying the interaction of HBP with these cells are unknown. Affinity isolation and enzymatic degradation demonstrated that HBP released from human neutrophils binds to endothelial cell-surface proteoglycans, such as syndecans and glypican. Flow cytometry indicated that a significant fraction of proteoglycan-bound HBP is taken up by the endothelial cells, and we used radiolabeled HBP to determine the internalization rate of surface-bound HBP. Confocal and electron microscopy revealed that internalized HBP is targeted to perinuclear compartments of endothelial cells, where it colocalizes with mitochondria. Western blotting of isolated mitochondria from HBP-treated endothelial cells showed that HBP is present in 2 forms - 28 and 22 kDa. Internalized HBP markedly reduced growth factor deprivation-induced caspase-3 activation and protected endothelial cells from apoptosis, suggesting that uptake and intracellular routing of exogenous HBP to mitochondria contributes to the sustained viability of endothelial cells in the context of locally activated neutrophils.

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publishing date
type
Contribution to journal
publication status
published
keywords
Antimicrobial Cationic Peptides, Apoptosis/drug effects, Biological Transport, Blood Proteins/metabolism, Carrier Proteins/metabolism, Cells, Cultured, Chromatography, Affinity, Endothelium, Vascular/cytology, Heparin/metabolism, Humans, Kinetics, Leukotriene B4/pharmacology, Mitochondria/metabolism, N-Formylmethionine Leucyl-Phenylalanine/pharmacology, Neutrophils/physiology, Proteoglycans/isolation & purification, Recombinant Proteins/metabolism, Tetradecanoylphorbol Acetate/pharmacology, Umbilical Veins
in
Journal of Clinical Investigation
volume
104
issue
7
pages
885 - 894
publisher
The American Society for Clinical Investigation
external identifiers
  • pmid:10510329
  • scopus:0032696674
ISSN
0021-9738
DOI
10.1172/JCI6671
language
English
LU publication?
yes
id
13589d7b-0714-4900-89c7-37c5b726ab70
date added to LUP
2018-08-27 13:54:12
date last changed
2024-04-15 10:33:06
@article{13589d7b-0714-4900-89c7-37c5b726ab70,
  abstract     = {{<p>Neutrophil-borne heparin-binding protein (HBP) is a multifunctional protein involved in the progression of inflammation. HBP is stored in neutrophil granules and released upon stimulation of the cells in proximity to endothelial cells. HBP affects endothelial cells in multiple ways; however, the molecular and cellular mechanisms underlying the interaction of HBP with these cells are unknown. Affinity isolation and enzymatic degradation demonstrated that HBP released from human neutrophils binds to endothelial cell-surface proteoglycans, such as syndecans and glypican. Flow cytometry indicated that a significant fraction of proteoglycan-bound HBP is taken up by the endothelial cells, and we used radiolabeled HBP to determine the internalization rate of surface-bound HBP. Confocal and electron microscopy revealed that internalized HBP is targeted to perinuclear compartments of endothelial cells, where it colocalizes with mitochondria. Western blotting of isolated mitochondria from HBP-treated endothelial cells showed that HBP is present in 2 forms - 28 and 22 kDa. Internalized HBP markedly reduced growth factor deprivation-induced caspase-3 activation and protected endothelial cells from apoptosis, suggesting that uptake and intracellular routing of exogenous HBP to mitochondria contributes to the sustained viability of endothelial cells in the context of locally activated neutrophils.</p>}},
  author       = {{Olofsson, A M and Vestberg, M and Herwald, H and Rygaard, J and David, G and Arfors, K E and Linde, V and Flodgaard, H and Dedio, J and Müller-Esterl, W and Lundgren-Akerlund, E}},
  issn         = {{0021-9738}},
  keywords     = {{Antimicrobial Cationic Peptides; Apoptosis/drug effects; Biological Transport; Blood Proteins/metabolism; Carrier Proteins/metabolism; Cells, Cultured; Chromatography, Affinity; Endothelium, Vascular/cytology; Heparin/metabolism; Humans; Kinetics; Leukotriene B4/pharmacology; Mitochondria/metabolism; N-Formylmethionine Leucyl-Phenylalanine/pharmacology; Neutrophils/physiology; Proteoglycans/isolation & purification; Recombinant Proteins/metabolism; Tetradecanoylphorbol Acetate/pharmacology; Umbilical Veins}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{885--894}},
  publisher    = {{The American Society for Clinical Investigation}},
  series       = {{Journal of Clinical Investigation}},
  title        = {{Heparin-binding protein targeted to mitochondrial compartments protects endothelial cells from apoptosis}},
  url          = {{http://dx.doi.org/10.1172/JCI6671}},
  doi          = {{10.1172/JCI6671}},
  volume       = {{104}},
  year         = {{1999}},
}