Vascular thrombogenicity induced by progressive LDL oxidation: protection by antioxidants.
Oxidative modification of LDL, which dysregulates the homeostasis between blood and vascular cells, and alterations of endothelial function are considered among the early events in the pathogenesis of atherosclerosis. This study was designed to evaluate the impact of progressive LDL oxidation on the thrombotic response both in vitro and in vivo, and to address the potential effect of antioxidants. Tissue factor was induced by progressive LDL oxidation in HUVEC, and this event was in parallel to the appearance of the apoptotic phenotype. Both these phenomena were mediated by ERK1/2 activation and were prevented by LDL pre-enrichment with antioxidants. In contrast, antioxidants failed to affect tPA and PAI-1 secretion, which was increased by LDL, either native or oxidized. Tissue factor-pathway inhibitor was also increased upon HUVEC exposure to progressively oxidized LDL. LDL, in the presence of an oxidative agent, trigger a thrombogenic response in vivo, mostly TF-dependent, in an in situ model of platelet deposition. This effect was markedly attenuated when LDL were enriched with antioxidants. It can be concluded that vascular thrombogenicity is induced by progressive LDL oxidation and that alterations of the antioxidant/oxidant balance of the LDL particle in favor of the antioxidant tone are protective against the thrombotic response triggered by oxidative stress. The extrapolation of these data in a clinical setting, even if not easy, offers potential insights for the use of antioxidants in the prevention of thrombotic complications associated with atherothrombosis.
Banfi
Cristina
C
Department of Pharmacological Sciences, E Grossi Paoletti Center, University of Milan, Milan, Italy.
Camera
Marina
M
Giandomenico
Giovanna
G
Toschi
Vincenzo
V
Arpaia
Magda
M
Mussoni
Luciana
L
Tremoli
Elena
E
Colli
Susanna
S
D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D010084:Oxidation-Reduction; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis; D013925:Thromboplastin / Q000378:metabolism; D013927:Thrombosis / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis
D000975:Antioxidants; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D017395:Plasminogen Activator Inhibitor 1; C051928:lipoprotein-associated coagulation inhibitor; D013925:Thromboplastin; D010959:Tissue Plasminogen Activator