Influence of plasma lipoproteins on platelet aggregation in a normal male population.

Hassall, David G.; Forrest, Leysa; Bruckdorfer, K. Richard; Marenah, C B; Turner, Peter R.; Cortese, Claudio; Miller, N. E.; Lewis, B

doi:10.1161/01.atv.3.4.332

Cited by 73 publications

(26 citation statements)

References 24 publications

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“…The interplay between both elements is apparent from the notion that LDL particles markedly enhance the responsiveness of platelets to various aggregation-inducing agents (1)(2)(3)(4). These agonists mediate the release of growth factors, vasoactive substances, and chemotactic agents that are known to stimulate atherosclerotic plaque formation.…”

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confidence: 99%

Binding of Low Density Lipoprotein to Platelet Apolipoprotein E Receptor 2′ Results in Phosphorylation of p38MAPK

Korporaal

Relou

Eck

et al. 2004

Journal of Biological Chemistry

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Binding of low density lipoprotein (LDL) to platelets enhances platelet responsiveness to various aggregation-inducing agents. However, the identity of the platelet surface receptor for LDL is unknown. We have previously reported that binding of the LDL component apolipoprotein B100 to platelets induces rapid phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK ). Here, we show that LDL-dependent activation of this kinase is inhibited by receptor-associated protein (RAP), an inhibitor of members of the LDL receptor family. Confocal microscopy revealed a high degree of co-localization of LDL and a splice variant of the LDL receptor family member apolipoprotein E receptor-2 (apoER2) at the platelet surface, suggesting that apoER2 may contribute to LDL-induced platelet signaling. Indeed, LDL was unable to induce p38 MAPK activation in platelets of apoER2-deficient mice. Furthermore, LDL bound efficiently to soluble apoER2, and the transient LDL-induced activation of p38 MAPK was mimicked by an anti-apoER2 antibody. Association of LDL to platelets resulted in tyrosine phosphorylation of apoER2, a process that was inhibited in the presence of PP1, an inhibitor of Src-like tyrosine kinases. Moreover, phosphorylated but not native apoER2 co-precipitated with the Src family member Fgr. This suggests that exposure of platelets to LDL induces association of apoER2 to Fgr, a kinase that is able to activate p38 MAPK . In conclusion, our data indicate that apoER2 contributes to LDL-dependent sensitization of platelets. Platelets and low density lipoproteins (LDL)1 are key elements in the development of atherothrombotic complications.The interplay between both elements is apparent from the notion that LDL particles markedly enhance the responsiveness of platelets to various aggregation-inducing agents (1-4). These agonists mediate the release of growth factors, vasoactive substances, and chemotactic agents that are known to stimulate atherosclerotic plaque formation. Sensitization of platelets by LDL involves the major LDL constituent apolipoprotein B100 (apoB100) (5), a 4563 amino acid protein that is wrapped around the LDL particle (6). LDL particles are recognized by the classical hepatic LDL receptor (LDL-R) through the apoB100 moiety, and in particular through a region within the apoB100 protein that is enriched in positively charged amino acids, the so-called B-site (7). Like LDL, a synthetic peptide mimicking this B-site associates to the platelet surface (5). Moreover, this peptide interferes with binding of LDL to platelets (5), suggesting that both elements share similar binding sites. This possibility is supported by the observation that binding of either LDL or the B-site peptide to the platelet results in a near immediate activation of the intracellular enzyme p38 mitogen-activated protein kinase (p38 MAPK ) (5, 8). Activation of this Ser/Thr kinase is associated with downstream phosphorylation and activation of cytosolic phospholipase A 2 , which leads to the formation of thromboxane A 2 (9, 10). Fi...

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confidence: 99%

Binding of Low Density Lipoprotein to Platelet Apolipoprotein E Receptor 2′ Results in Phosphorylation of p38MAPK

Korporaal

Relou

Eck

et al. 2004

Journal of Biological Chemistry

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“…LDL exhibits a synergistic action on thrombin-induced platelet activation [2] and plasma levels of LDL have been correlated with enhanced sensitivity of platelets to aggregation induced by adrenaline [3]. Platelets prepared from patients with various types of hypercholesterolemia also show increased responsiveness to thrombin [4,5).…”

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Rapid activation of human platelets by low concentrations of low‐density lipoprotein via phosphatidylinositol cycle

Knorr

Locher

Vogt

et al. 1988

European Journal of Biochemistry

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The interaction of low-density lipoprotein (LDL) with the human platelet was investigated with regard to saturable high-affinity binding, shape change, cytosolic free Ca2+ concentration, phosphatidylinositol (PtdIns) turnover, and thromboxane Bz biosynthesis. The experiments show that LDL, at a concentration approximately 100 times lower than in plasma, causes platelet activation concomitantly with stimulation of the PtdIns cycle and thromboxane B2 formation, similarly to other activators of platelets. The effects of LDL were inhibited by highdensity lipoprotein. The results suggest that activation of platelets by low concentrations of LDL may play a role in pathophysiological conditions and that platelet can serve as a model for studying the influence of LDL on various target cells.Low-density lipoprotein (LDL) binds with high affinity to blood platelets; the Kd of this binding is in the nanomolar range, whereas the concentrations of the lipoprotein in plasma are one or two orders of magnitude higher [l]. LDL exhibits a synergistic action on thrombin-induced platelet activation [2] and plasma levels of LDL have been correlated with enhanced sensitivity of platelets to aggregation induced by adrenaline [3]. Platelets prepared from patients with various types of hypercholesterolemia also show increased responsiveness to thrombin [4,5).A recent review indicates the importance of phosphoinositol-derived messenger molecules during platelet activation associated with the elevation of intracellular free Ca2 + concentration [Ca2+Ii [6]. Two major questions arise from these studies. a) Do LDL and other common agonists share the same activation pathways in platelets leading to elevation of [Ca2+Ii and shape change? Is it possible that there is an analogy between the mechanism of action of LDL and other platelet agonists? b) What are the concentrations of LDL required for optimal activation of platelets and how do these levels compare with physiological levels?In this context it should be considered that LDL is found not only in plasma but also in the extravascular fluids, where it is present at a much lower concentration owing to the diffusion barrier offered by the endothelium [7,8]. In addition, Therefore, it is of interest to know whether small concentrations of the lipoprotein, comparable to those occurring in the extravascular space, can cause cellular activation. Platelets were chosen since they are thought to be a valuable model for less-accessible target cells in the investigation of certain clinical disorders [l, 12-141. In this study we investigated the events associated with the activation of platelets by LDL. We show that LDL initiates the cascade of platelet activation in the same way as other platelet agonists such as thrombin; more importantly these effects were found to occur at LDL levels approximately 100-fold lower than the physiological concentrations in plasma. MATERIALS AND METHODS Materialsmy0-[2-~H] Inositol(l6.3 Ci/mmol), 32Pi (1 mCi/ml), 1251-thromboxane B2 and thromboxane B2 antiserum were pu...

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“…9 Platelet aggregability has been shown to decrease with decreasing levels of LDL in patients with familial hyperlipidemia and in normolipidemic males. 10,11 HMG-CoA reductase inhibitors, such as lovastatin and pravastatin, lower LDL cholesterol, 12,13 which should result in decreased platelet sensitivity to aggregation. However, the actual effect of HMG-CoA reductase inhibitors on platelets is unclear.…”

Section: Discussionmentioning

confidence: 99%

Combination of Fosinopril and Pravastatin Decreases Platelet Response to Thrombin Receptor Agonist in Monkeys

Hale

Craver

Berrier

et al. 1998

ATVB

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Abstract-Both angiotensin-converting enzyme (ACE) inhibitors and 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors have been shown to decrease cardiovascular morbidity and mortality. Results from clinical trials have suggested that HMG-CoA reductase inhibition might exert a beneficial effect independent of its lipid-lowering effect, and ACE inhibition may exert a benefit independent of blood-pressure lowering. To test the hypothesis that such an effect might be mediated by alteration in platelet reactivity, we studied 55 monkeys receiving both, 1, or neither of the ACE inhibitor fosinopril and the HMG-CoA reductase inhibitor pravastatin. Platelet responsiveness to collagen and to the thrombin receptor agonist (TRA) SFLRRN-NH 2 was determined by aggregometry. For each agonist, the maximum rate and extent of aggregation were measured for each dose, and the concentration required for half-maximal response (C 50 ) was determined. Each drug, when given alone, slightly decreased the dose of agonist required to produce 50% response in the rate and extent of platelet aggregation relative to control. The combination of the 2 drugs, however, produced a significant increase in the dose of TRA required to produce 50% response in the rate and extent of aggregation relative to either drug alone or the control group. This was not true for collagen. The magnitude of the change relative to the control group, 47% for rate and 30% for extent of aggregation, could confer considerable protection by changing the threshold for thrombin-induced platelet aggregation and, thus, decrease thrombosis. (Arterioscler Thromb Vasc Biol. 1998;18:1643-1646.)Key Words: angiotensin-converting enzyme inhibitors Ⅲ platelet aggregation Ⅲ 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors C ardiovascular disease is the leading cause of death in the United States. 1 Most of the morbidity and mortality of this disease results from the rupture of atherosclerotic plaques in the vessel wall. This event leads to exposure of the thrombogenic inner components of the plaque to circulating blood, resulting in platelet activation and aggregation and activation of the coagulation system. Subsequently, a thrombus forms.2 The use of angiotensin-converting enzyme (ACE) inhibitors and lipid-lowering drugs has decreased cardiovascular morbidity and mortality below that expected from the resulting mild reduction in blood pressure and minor reduction in severity of coronary stenosis.2-4 Therefore, in addition to their well-known actions, these drugs probably have other protective effects on the processes that lead to cardiovascular disease and thrombosis. It is possible that these drugs may affect platelet function.In this randomized trial, we studied platelet responsiveness to collagen and a thrombin receptor agonist (TRA) in monkeys that were treated with an ACE inhibitor, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, both drugs, or neither drug. Methods MaterialsThe highly purified peptide TRA SFLRRN-NH 2 (PMIS387) wa...

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Influence of plasma lipoproteins on platelet aggregation in a normal male population.

Cited by 73 publications

References 24 publications

Binding of Low Density Lipoprotein to Platelet Apolipoprotein E Receptor 2′ Results in Phosphorylation of p38MAPK

Binding of Low Density Lipoprotein to Platelet Apolipoprotein E Receptor 2′ Results in Phosphorylation of p38MAPK

Rapid activation of human platelets by low concentrations of low‐density lipoprotein via phosphatidylinositol cycle

Combination of Fosinopril and Pravastatin Decreases Platelet Response to Thrombin Receptor Agonist in Monkeys

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