Low-density lipoprotein and its effect on human blood platelets

Relou, Ingrid A.M.; Hackeng, Christian M.; Akkerman, J. W. N.; Malle, Ernst

doi:10.1007/s00018-003-2249-y

Cited by 79 publications

(69 citation statements)

References 104 publications

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“…[41][42][43] The activation process could potentially be mediated by VWF, since LDL has been shown to release VWF from EC. 44 46 Additionally, studies in LDLR Ϫ/Ϫ /VWF Ϫ/Ϫ mice demonstrated a reduction in atherosclerotic lesion development in regions of the aorta exposed to turbulent flow.…”

Section: Discussionmentioning

confidence: 99%

A fibrinogen deficiency accelerates the initiation of LDL cholesterol–driven atherosclerosis via thrombin generation and platelet activation in genetically predisposed mice

Iwaki

Sandoval-Cooper

Brechmann

et al. 2006

Blood

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IntroductionMouse models of atherosclerosis have vastly improved with the advent of in vivo gene manipulation technologies. On normal low-fat diets, the plasma cholesterol of mice is primarily packaged in the high-density lipoprotein (HDL) fraction. In contrast, humans have higher resting plasma total cholesterol (total-C) levels, and about 70% of the cholesterol is contained in the low-density lipoprotein (LDL) fraction. Several factors may contribute to these differences. Mice secrete both apolipoprotein (apo)B-100 and apoB-48 containing very low density lipoproteins (VLDL), which are synthesized in the liver. 1 In contrast, humans secrete only apoB-100 containing VLDL, 2 because humans do not express the apoB editing catalytic polypeptide-1 (apobec1) in liver. 3 ApoB-48 is produced from apoB-100 by an apobec1-catalyzed editing process that generates an in-frame stop codon in apoB-100. The C-terminus of apoB-100, absent in apoB-48, is essential for binding to the LDL receptor (Ldlr). Additionally, apoB-48-positive LDL also contains apoE, and this LDL particle is rapidly cleared by the apoE receptor instead of the Ldlr.A major mouse model for the study of atherosclerosis is the apoE-deficient (APOE Ϫ/Ϫ ) line. These mice present with severe hypercholesterolemia on a normal chow diet and develop spontaneous atherosclerosis. 4,5 However, in APOE Ϫ/Ϫ mice, the plasma cholesterol is mainly associated with the VLDL and intermediatedensity lipoprotein (IDL) fractions. Thus, these mice are models of human type III hyperlipidemia. Contrarily, in human atherosclerosis, type IIa hypercholesterolemia is frequently observed, with elevated plasma LDL cholesterol (LDL-C) due to reduced efficiency of the Ldlr. To attempt to represent this latter state, LDLR Ϫ/Ϫ mice were generated. 6 However, these mice demonstrate only a moderate elevation of plasma total-C levels, and they do not develop spontaneous atherosclerosis on a normal chow diet. 6 Mouse liver can express apobec1, and about 70% of its VLDL contains apoB-48, with 30% apoB-100. 1 Thus, most of the LDL in mice is apoB-48 positive and is not dependent on the Ldlr for its clearance. On the other hand, LDLR Ϫ/Ϫ mice are hyperlipidemic, 7 and this property leads to spontaneous plaque formation in the aorta when these mice are placed on high-fat diets. 8 Nonetheless, LDLR Ϫ/Ϫ mice also present with high VLDL-C. 7 Thus, in terms of lipid metabolism, neither of these strains reflects the lipid profiles found in human type IIa familial hypercholesterolemia.To resolve the limitations of LDLR Ϫ/Ϫ mice, the APOBEC1 Ϫ/Ϫ mouse was developed. This deficiency does not result in elevations of plasma total-C and triglycerides (TG), 9 but mice with a double deficiency of Ldlr and apobec1 (L Ϫ/Ϫ /A Ϫ/Ϫ ) have high levels of LDL-C when fed a normal chow diet. Spontaneous atherosclerosis formation in the aorta also is found. 10 For personal use only. on May 9, 2018. by guest www.bloodjournal.org FromIn addition to functioning in clot formation, in some mammalian species fibrinogen (Fg) and...

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Section: Discussionmentioning

confidence: 99%

A fibrinogen deficiency accelerates the initiation of LDL cholesterol–driven atherosclerosis via thrombin generation and platelet activation in genetically predisposed mice

Iwaki

Sandoval-Cooper

Brechmann

et al. 2006

Blood

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“…LDL enhances platelet function and increases sensitivity of platelets to several naturally occurring agonists. LDL sensitizes platelets via binding of apolipoprotein B-100 to a receptor on the platelet membrane and via transfer of lipids to the platelet membrane [22]. Thus, increased platelet susceptibility to several agonists may enhance the risk of ischemic stroke.…”

Section: Discussionmentioning

confidence: 99%

The Influence of Hyperlipidemia on Platelet Activity Markers in Patients after Ischemic Stroke

Pawełczyk¹,

Baj²,

Chmielewski³

et al. 2008

Cerebrovasc Dis

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Background: To investigate the relationship between hyperlipidemia and platelet activation markers – platelet and soluble P-selectin (sP-selectin), and platelet-derived microparticles (PDMPs) – in patients after ischemic stroke. Methods: 41 patients after ischemic stroke (>3 months) confirmed by CT were divided into 2 groups: with hyperlipidemia (HL, n = 21) and normolipidemia (NL, n = 20). Twenty healthy subjects served as controls. CD62P-positive platelets and PDMPs in whole blood were analyzed by the use of a flow cytometer and anti-CD61 and anti-CD62P monoclonal antibodies. Platelets were activated by thrombin (0.08 units). The level of sP-selectin in serum was measured by ELISA. Results: We observed a significantly higher CD62P expression and percentage of CD62P-positive resting and thrombin-activated platelets in the HL as compared to the NL group. The sP-selectin concentration was also significantly higher in HL than NL subjects (p < 0.05). Moreover, we observed a significantly higher percentage of PDMPs in patients after stroke (NL: p < 0.05; HL: p = 0.005) in comparison with the control group. Conclusions: Patients after stroke present symptoms of platelet hyperreactivity. HL in the patients may be a risk factor for vascular events due to the increase in platelet activation.

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“…Several LDL and oxidized LDL receptors may function as signal-transduction receptors, and CD36 (GPIV) is a more likely candidate. 24,25,27 The ability of fatty acid-free albumin and indomethacin to block partially HOCl-LDL-induced aggregation, also suggests a role for lipid mediators, 61,77,78 whereas partial sensitivity to indomethacin indicates that PLA 2 activation and TxA 2 are not essential for HOCl-LDL stimulation of platelet function. These results suggest that several mechanisms exist which involve both initial activation pathways as well as events required for the stabilization of platelet aggregates.…”

Section: Platelet Aggregation Bymentioning

confidence: 99%

“…18,19 Cell-associated lipoxygenase is also implicated in LDL oxidation by formation of reactive aldehydes. 2 n-LDL itself can potentiate platelet function, [20][21][22][23][24] complicating analyses of the roles of n-LDL versus ox-LDL in the pathogenesis of atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

LDL oxidized by hypochlorous acid causes irreversible platelet aggregation when combined with low levels of ADP, thrombin, epinephrine, or macrophage-derived chemokine (CCL22)

Coleman

Polanowska-Grabowska

Marcinkiewicz

et al. 2004

Blood

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The in vitro oxidation of low-density lipoprotein (LDL) by hypochlorous acid produces a modified form (HOCl-LDL) capable of stimulating platelet function. We now report that HOCl-LDL is highly effective at inducing platelet function, causing stable aggregation and α-granule secretion. Such stimulation depended on the presence of low levels of primary agonists such as adenosine diphosphate (ADP) and thrombin, or others like epinephrine (EPI) and macrophage-derived chemokine (MDC, CCL22). Agonist levels, which by themselves induced little or reversible aggregation, caused strong stable aggregation when combined with low levels of HOCl-LDL. Platelet activation by HOCl-LDL and ADP (1 μM) caused P-selectin (CD62P) exposure, without serotonin or adenosine triphosphate (ATP) secretion. Intracellular calcium levels rose slowly (from 100 to 200 nM) in response to HOCl-LDL alone and rapidly when combined with ADP to about 300 nM. p38 mitogen-activated protein kinase (MAPK) became phosphorylated in response to HOCl-LDL alone. This phosphorylation was not blocked by the protein kinase C (PKC) inhibitor bisindolylmaleimide, which reduced the extent of aggregation and calcium increase. However, the p38 MAPK inhibitor SB203580 blocked platelet aggregation and phosphorylation of p38 MAPK. These findings suggest that HOCl-LDL exposed during atherosclerotic plaque rupture, coupled with low levels of primary agonists, can rapidly induce extensive and stable thrombus formation. (Blood. 2004;104:380-389)

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Low-density lipoprotein and its effect on human blood platelets

Cited by 79 publications

References 104 publications

A fibrinogen deficiency accelerates the initiation of LDL cholesterol–driven atherosclerosis via thrombin generation and platelet activation in genetically predisposed mice

A fibrinogen deficiency accelerates the initiation of LDL cholesterol–driven atherosclerosis via thrombin generation and platelet activation in genetically predisposed mice

The Influence of Hyperlipidemia on Platelet Activity Markers in Patients after Ischemic Stroke

LDL oxidized by hypochlorous acid causes irreversible platelet aggregation when combined with low levels of ADP, thrombin, epinephrine, or macrophage-derived chemokine (CCL22)

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