Role of reactive oxygen species and p38 MAPK in the induction of the pro-adhesive endothelial state mediated by IgG from patients with anti-phospholipid syndrome.
The association of the presence of anti-phospholipid antibodies (aPL) with thrombosis characterizes the anti-phospholipid syndrome (APS). The activation of the endothelium is a key event in the establishment of the thrombophilic state. However, the intracellular mechanisms leading to endothelial dysfunction are not fully elucidated. We investigated the role of reactive oxygen species (ROS) in the pro-adhesive state elicited by aPL and studied ROS-dependent downstream signaling pathways. Independent incubation of human umbilical vein endothelial cells (HUVEC) with IgG (IgG-APS) from 12 APS patients caused a large and sustained increase in ROS, which was prevented by the antioxidants vitamin C and N-acetyl-L-cysteine. ROS inhibition observed in the presence of diphenylene iodonium and rotenone indicated an involvement of a membrane-bound oxidase and the mitochondrial transport chain as sources of ROS. ROS acted as a second messenger by activating the p38 mitogen-activated protein kinase and its subsequent target, the stress-related transcription factor activating transcription factor-2 (ATF-2). ROS controlled the up-regulation of vascular cell adhesion molecule-1 expression by IgG-APS-stimulated HUVEC and the increase in THP-1 monocytic cells adhesion. The IgG-APS-mediated oxidative stress was observed irrespective of the clinical and biological criterions of the patients studied here. Taken together, these data indicate that the oxidative stress induced by IgG-APS is a key intracellular event that might contribute to the thrombotic complications of APS by controlling the endothelial adhesive phenotype.
Simoncini
Stéphanie
S
INSERM U608 Physiopathologie de l'Endothélium, Université de la Méditerranée, UFR de Pharmacie, 27 Bd Jean Moulin, 13385 Marseille Cedex 5, France.
Sapet
Cédric
C
Camoin-Jau
Laurence
L
Bardin
Nathalie
N
Harlé
Jean-Robert
JR
Sampol
José
J
Dignat-George
Françoise
F
Anfosso
Francine
F
D000975:Antioxidants / Q000378:metabolism; D016736:Antiphospholipid Syndrome / Q000276:immunology* / Q000378:metabolism*; D002448:Cell Adhesion / Q000276:immunology / Q000502:physiology; D004727:Endothelium / Q000276:immunology / Q000378:metabolism; D007074:Immunoglobulin G / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000975:Antioxidants; D007074:Immunoglobulin G; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; D048051:p38 Mitogen-Activated Protein Kinases