Vascular thrombogenicity induced by progressive LDL oxidation: protection by antioxidants

Abstract

SummaryOxidative 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.

PAI‐1 activity, but not fibrinogen or von Willebrand factor, is inversely related to LDL particle size in type 2 diabetes

“…The observed relationship between PAI-1 and the small LDL phenotype could be a direct one or could merely be the reflection of the relationship of both factors with a 'third' component such as triglycerides or insulin resistance. Evidence for a potential direct relationship stems from in vitro studies showing that oxidized LDL particles stimulate PAI-1 secretion from endothelial cells [30,31] and vascular smooth muscle cells [32]. Since small dense LDL particles are particularly prone to oxidative modification [33][34][35], this could partially explain the relationship between the small LDL phenotype and increased levels of PAI-1 found in our study.…”

Oxidative Status and Lipid Profile in Metabolic Syndrome: Gender Differences

“…ApoA is the main component of HDL, representing 65% of the content. 16 Both ApoA, the major HDL apolipoprotein, and sphingosine-1-phosphate, a minor bioactive lipid, have been proposed to contribute signifi cantly to HDL-mediated cytoprotection. Altered conformation of ApoA-1 in small HDL particles in metabolic syndrome may result in their defi cient biological acitivity, thereby weakening the defense of HDL antiapoprotic activity from density and ApoA-I content.…”

Protective effect of dietary fenugreek (Trigonella foenum-graecum) seeds and garlic (Allium sativum) on induced oxidation of low-density lipoprotein in rats

“…The important corollary is that, inhibition of such oxidation would reduce the progression of atherosclerosis, independent of reduction of other factors such as elevated LDL cholesterol levels [24,25]. Oxidative modifications of LDL, which dysregulate the homeostasis between blood and vascular cells and alteration in endothelial function are considered to be the early events in the pathogenesis of atherosclerosis [26]. LDL oxidation can lead to its subsequent aggregation, which further increases cellular cholesterol accumulation [27].…”