The extracellular adherence protein from Staphylococcus aureus abrogates angiogenic responses of endothelial cells by blocking Ras activation.
The extracellular adherence protein (Eap), a broad-spectrum adhesin secreted by Staphylococcus aureus, was previously shown to curb acute inflammatory responses, presumably through its binding to endothelial cell (EC) ICAM-1. Examining the effect of Eap on endothelial function in more detail, we here show that, in addition, Eap functions as a potent angiostatic agent. Concomitant treatment of EC with purified Eap resulted in the complete blockage of the mitogenic and sprouting responses elicited by vascular endothelial growth factor (VEGF)165 or basic fibroblast growth factor (bFGF). Moreover, the induction of tissue factor and decay-accelerating factor were repressed by Eap, as determined by qRT-polymerase chain reaction (qRT-PCR), with a corresponding reduction in Egr-1 protein up-regulation seen. This angiostatic activity was accompanied by a corresponding inhibition in ERK1/2 phosphorylation, while activation of p38 was not affected. Inhibition occurred downstream of tyrosine kinase receptor activation, as comparable effects were seen on TPA-induced ERK1/2 phosphorylation. Similar to previously described angiostatic agents like angiopoietin-1 or the 16-kDa prolactin fragment, Eap blockage of the Ras/Raf/MEK/ERK cascade was localized by pull-down assay at the level of Ras activation. Eap's combined anti-inflammatory and antiangiogenic properties render this bacterial protein not only an important virulence factor during S. aureus infection but open new perspectives for therapeutic applications in pathological neovascularization.
Sobke
Astrid C S
AC
Institute of Medical Microbiology and Hygiene, University of Saarland Hospital, D-66421 Homburg/Saar, Germany. astrid.sobke@gmx.de
Selimovic
Dennis
D
Orlova
Valeria
V
Hassan
Mohamed
M
Chavakis
Triantafyllos
T
Athanasopoulos
Athanasios N
AN
Schubert
Uwe
U
Hussain
Muzaffar
M
Thiel
Gerald
G
Preissner
Klaus T
KT
Herrmann
Mathias
M
D001426:Bacterial Proteins / Q000378:metabolism / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D051966:Phospholipase C gamma / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D001426:Bacterial Proteins; C444739:Eap-N protein, Staphylococcus aureus; D016601:RNA-Binding Proteins; D042461:Vascular Endothelial Growth Factor A; D005346:Fibroblast Growth Factors; D019908:Proto-Oncogene Proteins c-raf; D020929:Mitogen-Activated Protein Kinase Kinases; D051966:Phospholipase C gamma; D018631:ras Proteins