The Importance of Oxidation or Glycosylation of Low-density Lipoproteins in Relation to Platelet Activation

Meraji, Shokoufeh; Moore, Carolyn E.; Skinner, Vernon; Bruckdorfer, K. Richard

doi:10.3109/09537109209013176

Cited by 27 publications

(19 citation statements)

References 27 publications

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“…Lipid-rich plaques are vulnerable and, on rupture, might expose thrombogenic LDL particles that activate circulating platelets, causing them to aggregate and form an intravascular plug that eventually leads to stroke and myocardial infarction (7). Indeed, previous studies indicate that oxidatively modified LDL stimulates platelets, mox-LDL being more active than heavily oxidized LDL (8,9).…”

mentioning

confidence: 99%

Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions

Siess

Zangl

Essler

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

385

425

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Oxidized low density lipoprotein (LDL) is a key factor in the pathogenesis of atherosclerosis and its thrombotic complications, such as stroke and myocardial infarction. It activates endothelial cells and platelets through mechanisms that are largely unknown. Here, we show that lysophosphatidic acid (LPA) was formed during mild oxidation of LDL and was the active compound in mildly oxidized LDL and minimally modified LDL, initiating platelet activation and stimulating endothelial cell stress-fiber and gap formation. Antagonists of the LPA receptor prevented platelet and endothelial cell activation by mildly oxidized LDL. We also found that LPA accumulated in and was the primary platelet-activating lipid of atherosclerotic plaques. Notably, the amount of LPA within the human carotid atherosclerotic lesion was highest in the lipid-rich core, the region most thrombogenic and most prone to rupture. Given the potent biological activity of LPA on platelets and on cells of the vessel wall, our study identifies LPA as an atherothrombogenic molecule and suggests a possible strategy to prevent and treat atherosclerosis and cardiocerebrovascular diseases.

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mentioning

confidence: 99%

Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions

Siess

Zangl

Essler

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

385

425

View full text Add to dashboard Cite

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“…5 Native LDLs (nLDLs) reportedly stimulate human platelets, 6,7 but minimally modified LDLs rather than nLDLs may be responsible for these effects. 8,9 LDLs oxidized in vitro by various agents (oxLDLs) showed even more pronounced platelet activation. 10 Because activated platelets may themselves contribute to oxidative modification of LDLs, 11 the platelet-stimulatory effect of plasma lipoproteins is potentially a key event in atherogenesis.…”

mentioning

confidence: 99%

Modification of Protein Moiety of Human Low Density Lipoprotein by Hypochlorite Generates Strong Platelet Agonist

Volf

Bielek

Moeslinger

et al. 2000

ATVB

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Abstract-Conflicting reports exist about the effects of mildly or extensively oxidized low density lipoproteins (LDLs) on the reactivity of human platelets. This platelet response is mainly caused by modification of the protein and lipid moiety, giving rise to very differently modified species with hardly predictable properties. The aim of this study was to prepare oxidized LDL with modifications essentially restricted to the protein moiety and to determine the eventual platelet responses. We treated LDL at 0°C for 10 minutes with a 60-to 1000-fold molar excess of sodium hypochlorite in borate buffer in the presence of the radical scavenger butylated hydroxytoluene. Under these conditions, neither fragmentation of apolipoprotein B-100 nor formation of LDL aggregates was observed, and lipid oxidation products did not exceed the amount present in untreated LDLs. The degree of modification and the respective effects on platelet function were highly reproducible. Hypochlorite-modified LDLs act as strong platelet agonists, inducing morphological changes, dense granule release, and irreversible platelet aggregation. The evoked platelet effects are completely suppressed by inhibitors of the phosphoinositide cycle but not by EDTA or acetylsalicylic acid. Most likely, these effects are transmitted via high-affinity binding to a single class of sites, which does not recognize native or acetylated LDL. Obviously, modified lysines, and the secondary lipid modifications derived from them, are not essential for this interaction. We conclude that bioactive oxidized lipids are not directly involved in the stimulation of platelets by hypochlorite-modified LDLs. Key Words: atherosclerosis Ⅲ oxidized LDL Ⅲ apoB-100 Ⅲ human platelets Ⅲ platelet aggregation P latelet-vessel wall interaction (adhesion) and plateletplatelet interaction (aggregation) play a central role in vascular occlusion but are also involved in the earlier stages of development of atherosclerotic plaques. 1 Therefore, conditions leading to altered platelet function are accompanied with an enhanced risk of atherosclerosis and thrombosis. 2 Among others, severe disorders of plasma lipids lead to enhanced platelet reactivity. In particular, it has been known for Ͼ25 years that platelets from hyperlipidemic patients are hyperreactive. 3 Furthermore, LDLs from patients with homozygous familial hypercholesterolemia show enhanced susceptibility to oxidative modification, 4 thus generating a form that is substantially more atherogenic than unmodified LDLs. 5 Native LDLs (nLDLs) reportedly stimulate human platelets, 6,7 but minimally modified LDLs rather than nLDLs may be responsible for these effects. 8,9 LDLs oxidized in vitro by various agents (oxLDLs) showed even more pronounced platelet activation. 10 Because activated platelets may themselves contribute to oxidative modification of LDLs, 11 the platelet-stimulatory effect of plasma lipoproteins is potentially a key event in atherogenesis.Free radicals as well as nonradical oxidants are involved in the oxidative modif...

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“…In contrast to nLDL, oxidatively modifi ed LDL induces rapid immediate platelet responses such as shape change and aggregation [16][17][18][19] . The platelet response appears to be dependent of the type of oxidation method used and the degree of oxidation of LDL.…”

Section: Mildly Oxidized Lipoproteins (Ldl Hdl) Stimulate Plateletsmentioning

confidence: 99%

“…The platelet response appears to be dependent of the type of oxidation method used and the degree of oxidation of LDL. Using cupper-or SIN-1 induced oxidation, mild oxidation has been shown to produce LDL particles with higher platelet-activating potency than strong oxidation [17,18] . Chemical characterization of mildly oxidized LDL (mox-LDL) showed no indication of protein modifi cation and only a minor decrease of polyunsaturated fatty acids in mox-LDL, but protein modifi cation and an almost complete disappearance of polyunsaturated fatty acids in ox-LDL [18,35] .…”

Section: Mildly Oxidized Lipoproteins (Ldl Hdl) Stimulate Plateletsmentioning

confidence: 99%

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Platelet Interaction with Bioactive Lipids Formed by Mild Oxidation of Low-Density Lipoprotein

Siess¹

2006

Pathophysiol Haemos Thromb

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The Importance of Oxidation or Glycosylation of Low-density Lipoproteins in Relation to Platelet Activation

Cited by 27 publications

References 27 publications

Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions

Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions

Modification of Protein Moiety of Human Low Density Lipoprotein by Hypochlorite Generates Strong Platelet Agonist

Platelet Interaction with Bioactive Lipids Formed by Mild Oxidation of Low-Density Lipoprotein

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