Oxidized membrane vesicles and blebs from apoptotic cells contain biologically active oxidized phospholipids that induce monocyte-endothelial interactions.
Membrane vesicles (MVs) released from activated cells and blebs from apoptotic cells are increased in patients with vascular disease and in those with atherosclerotic lesions, and their contribution to inflammatory reactions has been suggested. At sites of inflammation, MVs could serve as rapidly available substrates for peroxidation, carry oxidized compounds to activate other cells, and amplify inflammation. Here, we show that MVs released from tert-butyl hydroperoxide-treated endothelial cells (ECs) and apoptotic blebs, but not MVs from Ca(2+) ionophore-treated ECs, stimulate monocyte adhesion to ECs, an important step in atherogenesis. We show that oxidized phospholipids, such as the previously identified 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine (POVPC), are responsible for biological activity in MVs and apoptotic blebs. Natural antibodies from apolipoprotein E-null mice that recognize POVPC also recognize oxidized MVs, and pretreatment of MVs with these antibodies inhibits their ability to activate ECs. Furthermore, the biological activity of oxidized MVs is inhibited by platelet-activating factor receptor antagonists, which have been shown to inhibit the action of POVPC. Taken together, we show that oxidized MVs and apoptotic blebs stimulate ECs to specifically bind monocytes, with oxidized phospholipids (POVPC) being the active principle. In addition to oxidized lipoproteins, oxidized MVs and apoptotic blebs may play an important role in chronic inflammatory diseases, such as atherosclerosis.
Huber
Joakim
J
Department of Vascular Biology and Thrombosis Research, University of Vienna, Austria.
Vales
Anja
A
Mitulovic
Goran
G
Blumer
Michael
M
Schmid
Rainer
R
Witztum
Joseph L
JL
Binder
Bernd R
BR
Leitinger
Norbert
N
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects*; D022162:Cytoplasmic Vesicles / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology; D010084:Oxidation-Reduction; D010742:Phospholipid Ethers; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014471:Umbilical Veins / Q000166:cytology; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
C400184:1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine; D010742:Phospholipid Ethers; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D020122:tert-Butylhydroperoxide