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Hypertension. 2007;50:276-283
Published online before print June 4, 2007, doi: 10.1161/HYPERTENSIONAHA.107.089854
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(Hypertension. 2007;50:276.)
© 2007 American Heart Association, Inc.

Brief Reviews

Effects of Native and Modified Low-Density Lipoproteins on Monocyte Recruitment in Atherosclerosis

Christian A. Gleissner; Norbert Leitinger; Klaus Ley

From the Departments of Biomedical Engineering (C.A.G., K.L.), Pharmacology (N.L.), Molecular Physiology and Biological Physics (K.L.), and the Robert M. Berne Cardiovascular Research Center (C.A.G., N.L., K.L.), University of Virginia, Charlottesville.

Correspondence to Klaus Ley, MD, Robert M. Berne Cardiovascular Research Center, University of Virginia, P.O. Box 801394, Charlottesville, VA 22908. E-mail klausley{at}virginia.edu


*    Introduction
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 *Introduction
down arrowMonocyte Recruitment to the...
 down arrowNative and Modified Forms...
 down arrowEffects of Modified Forms...
 down arrowEffects of Native LDL
 down arrowConclusion and Future Directions
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Atherosclerosis is a chronic inflammatory disease of the arterial wall1–3 with enormous epidemiological relevance.4,5 Recruitment of monocytes to the vascular wall is a key feature in the pathogeneses of atherosclerotic lesions. Through a complex cascade of interactions between adhesion molecules and chemotactic factors, monocytes enter the subendothelial space, where they develop into macrophages, foam cells, and dendritic cells under the influence of cytokines, growth factors, and lipoproteins.6–8 Foam cells eventually undergo secondary necrosis and form the lipid core of advanced atherosclerotic plaques. When exposed by rupture or erosion, it triggers acute thrombotic events leading to myocardial infarction and strokes.9

Elevated serum levels of low-density lipoprotein (LDL) (see the Table for abbreviations) are a major risk factor for the development of atherosclerosis.4 Apart from epidemiological evidence for the proatherogenic role of lipoproteins, mechanistic studies suggest that they play a role in monocyte recruitment to the vessel wall and the progression of macrophages to foam cells. LDL does not only occur in its native form, but modified forms of LDL—eg, by oxidation, aggregation, or other processes—are thought to be even more proatherogenic.10–13


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  		Abbreviations Used in the Text

Even though numerous reviews have focused on monocyte recruitment to the arterial wall14–16 or on effects of LDL on foam cell formation7,14 in atherogenesis, no recent review has specifically addressed the effects of native and modified LDL on monocyte recruitment to the vessel wall. Here, we discuss the molecular effects of LDL on monocyte recruitment to the arterial wall as a crucial step in the pathogenesis of atherosclerosis.


*    Monocyte Recruitment to the Arterial Wall
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Recruitment of leukocytes to the vessel wall is a multi-step process consisting of capture, rolling, arrest, adhesion, and transmigration through the endothelium. These steps require expression and interaction of adhesion molecules and their ligands on the vascular endothelium and on the monocyte surface. Four groups of adhesion molecules have been identified in this process: selectins, selectin ligands, integrins, and immunoglobulin-like adhesion molecules.17,18 In addition to these adhesion molecules, chemokines play an important role in monocyte recruitment.19 The mechanisms of monocyte recruitment to the vessel wall have been reviewed.14,16


*    Native and Modified Forms of LDL
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LDL is a heterogeneous class of lipoprotein particles consisting of a hydrophobic core containing triglycerides and cholesterol esters in a hydrophilic shell of phospholipids, free cholesterol, and apolipoproteins (predominantly B-100), the latter acting as ligands for lipoprotein receptors. The density of LDL ranges from 1.019 to 1.063 g/mL, its diameter is between 20 and 25 nm.20 LDL binds to and is internalized by a specific LDL receptor (LDLR)21 expressed on endothelial cells, monocytes, macrophages, and smooth muscle cells in atherosclerotic lesions.22 LDLR expression is downregulated by elevated serum LDL levels.23

Apart from native LDL, modified forms of LDL occur in vitro and in vivo, displaying characteristics different from native LDL that make them even more atherogenic. LDL can be oxidized by exposure to copper salts or by coincubation with other cell types like endothelial cells, smooth muscle cells, monocytes, or macrophages expressing 5-, 12-, and 15-lipoxygenase.24,25 There is evidence for the presence of oxLDL in atherosclerotic lesions in humans.26 Enzymatic modification of LDL by hydrolytic enzymes has been discussed,27 and there is some evidence that enzymatically modified LDL may play a role in atherogenesis in vivo.28 Other ways of LDL modification are glycation13 and incorporation in immune complexes.11,13,29 LDL is thought to be modified in the subendothelial space even though modification in the blood stream cannot be completely ruled out10 (Figure 1). Depending on the degree of oxidation, minimally-modified LDL (mmLDL) can be differentiated from fully oxidized LDL (oxLDL).30


Figure 1
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  		Figure 1. Modification of low-density lipoproteins by various interventions. Binding of native LDL to the LDL receptor is mediated by apolipoprotein B (ApoB) (1). Modification of ApoB by (2) blocking of lysine residues through formation of Schiff bases, (3) fragmentation of ApoB by oxidation or enzymatic modification, (4) glycation, or (5) incorporation in immune complexes interferes with LDLR binding, thus modified LDL is bound and taken up by scavenger receptors (2–4). Immune complexes containing oxLDL bind to Fc{gamma} receptor or activate complement (5).

In contrast to native LDL, mmLDL is bound and internalized not only by the LDLR but also by a number of scavenger receptors, whereas oxLDL exclusively binds to scavenger receptors31 including scavenger receptor class A (SR-AI and SR-AII32), class B (CD3633,34), class D (CD6835), class E (oxidized LDL receptor [LOX-1]36), or class G CXCL16 (scavenger receptor that binds phosphatidylserine and oxidized lipoprotein SR-PSOX37). LDL incorporated in immune complexes is bound and internalized by the Fc{gamma} receptor or activates complement.29 LDLR and scavenger receptors are expressed in macrophages, and some are found in platelets and smooth muscle cells.22,38 Unlike LDLR, scavenger receptors are not downregulated by elevated serum LDL levels.


*    Effects of Modified Forms of LDL
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Modified forms of LDL like mmLDL and oxLDL are more proatherogenic than native LDL. mmLDL and oxLDL increase adherence of monocytes to the endothelium in vivo.39–41 In human fetal aortas, retention and oxidation of LDL has been demonstrated to precede accumulation of monocytes and formation of fatty streaks.42 Several mechanisms for increased monocyte recruitment attributable to presence of modified LDL in the arterial wall have been identified: (1) modified LDL enhances monocyte adhesion to the endothelium by inducing expression of adhesion molecules, chemotactic and growth factors in endothelial cells, (2) modified LDL exerts effects on monocytes inducing their adherence to the endothelium, and (3) modified LDL activates platelets, thereby promoting platelet-monocyte aggregates and increasing monocyte adherence to the endothelium (Figure 2).


Figure 2
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  		Figure 2. Schematic summary of effects of modified low-density lipoprotein on monocyte recruitment to the arterial wall (1): Induction of adhesion molecules (VCAM-1, ICAM-1, CS-1 containing form of fibronectin, JAM-C) and chemokines (CCL2, CXCL8) in endothelial cells, (2) induction of chemokines, chemokines receptors, and adhesion molecules in monocytes, (3) amplification of platelet activation in combination with other activators (ADP, thrombin). Question marks indicate that exact mechanisms are still unclear.

Endothelium
Two scavenger receptors mediate effects of oxLDL on endothelial cells: CD3643 and LOX-1.44 Intracellular events induced by oxLDL include upregulation of adenylate cyclase generating cAMP as second messenger, but there is no direct evidence for CD36 or LOX-1 to be involved.45 Ligation of LOX-1 induces NF{kappa}B in cultured human endothelial cells.45–48 Intracellular signaling in endothelial cells after stimulation with mmLDL involves protein kinase-C (PKC) ß,49 12-lipoxygenase,50 and intracellular free calcium.50

Depending on the degree of oxidation, LDL induces expression of P-selectin in human umbilical vein endothelial cells (HUVECs), which increases adhesion of monocytes.51 Exposure of human aortic endothelial cells (HAECs) to mmLDL increases cell surface P-selectin protein expression as measured by immunofluorescence but has no significant effect on P-selectin message.52 Exposure of human aortic endothelial cells to mmLDL suppresses transforming growth factor (TGF)-ß secretion through a LOX-1–dependent process; TGF-ß appears to inhibit oxLDL-dependent monocyte adhesion under static conditions.53

In HUVECs and HAECs, oxLDL enhances tumor necrosis factor (TNF)-{alpha}–induced expression of vascular cell adhesion molecule (VCAM)-1 with a peak at 6 hours but not E-selectin.54 VCAM-148 and intercellular adhesion molecule-1 (ICAM-1)48,53 expression in HAEC is increased after stimulation with oxLDL. 13-HPODE shows a similar effect, suggesting that this component of oxLDL might be responsible for the enhanced VCAM-1 and ICAM-1 expression.54 oxLDL increases adhesion of THP-1 cells (a human cell line derived from a patient with monocytic leukemia, which has phagocytotic capacities, produces lysozyme, and to some extent activates T cells55) to HAECs by 50% under static conditions which is reduced to below baseline by flow.48 Interestingly, VCAM-1 but not ICAM-1 expression is suppressed by flow. In vivo, endothelial VCAM-1 expression is rapidly induced by an atherogenic diet.56 In rabbits, induction of ICAM-1 expression in endothelial cells was confirmed beginning 24 hours after injection of native LDL, which was trapped and oxidized in the arterial wall as demonstrated by histological analysis.57 Conversely, lowering of lipids in rabbits resulted in reduction of endothelial VCAM-1 expression.58 These in vivo data support an effect of modified LDL on monocyte recruitment by upregulation of endothelial adhesion molecules.

Human secreted phospholipase A2 has been shown to hydrolyze LDL resulting in formation of lysophosphatidylcholine (lyso-PC), which has specific chemotactic effects on monocytes but not on resident macrophages.59 In cultured rabbit and human endothelial cells, lyso-PC induces ICAM-1 and VCAM-1 expression resulting in increased attachment of the monocytic cell lines THP-1 and U937 (a human histiocytic lymphoma cell line60).61 It has recently been shown that this modification of LDL can be achieved by human group X enzyme, one of the secreted phospholipases A2. Lyso-PC activates MAP kinase in HUVECs and induces doubling of ICAM-1, VCAM-1, and E-selectin expression resulting in significantly increased adhesion of monocytes under static conditions.62

Similarly, LDL modified by trypsin, cholesterol esterase, or neuraminidase induces monocyte adhesion and transmigration in vitro even more than oxLDL or native LDL, an effect mediated by upregulation of P-selectin, E-selectin, and ICAM-1.63 Immunoreactivity for enzymatically modified LDL was found in human atherosclerotic lesions supporting its role in atherogenesis.28 These results suggest that the effects of modified LDL depend on the result of modification (eg, fragmentation of apolipoprotein B).

mmLDL can induce monocyte adhesion to HAECs independently of VCAM-1 expression by interaction of connecting segment-1 (CS-1), an alternatively spliced form of fibronectin expressed on the endothelial surface, with {alpha}4ß1 integrin.64 Furthermore, junctional cell adhesion molecule-C (JAM-C) has been suggested to play a role in oxLDL-mediated increased adhesion of monocytes to HAECs. oxLDL significantly upregulates JAM-C expression in HUVECs, resulting in increased adherence and transmigration of THP-1 cells mediated by Mac-1 (CD11b/CD18) and ICAM-1.65

Coculture-modified LDL, which has biological and chemical properties comparable to those of mmLDL, induces expression of heme oxygenase-1 (HO-1) in HAECs cocultured with human aortic smooth muscle cells, an effect mediated by arachidonic acid-containing phospholipids66 but not by lyso-PC.67 HO-1 induction in endothelial cells inhibits monocyte transmigration potentially by increased levels of biliverdin, a HO-1 product known to inhibit chemotaxis.66 Induction of HO-1, which is known to have a number of antiatherogenic effects,68 might represent a protective mechanism of the endothelium.

Lipoprotein(a) (Lp(a)) and its apolipoprotein A have chemotactic effects on monocytes and induce monocyte adhesion through interaction with the ß2 integrin Mac-1 (CD11b/CD18).69 Apolipoprotein CIII has been identified to be one constituent of oxLDL responsible for enhanced adhesion of THP-1 cells to human saphenous vein endothelial cells (HSVECs) in a dose- and time-dependent manner. This effect is mediated by upregulation of ICAM-1 and VCAM-1 on the endothelium.49

Several studies have demonstrated that oxLDL itself can act as chemoattractant for monocytes and T cells.70,71 In addition, modified LDL induces a number of chemotactic and growth factors in various cell types. Thus, in endothelial cells modified LDL can induce release of CCL2 (MCP-1) and M-colony stimulating factor (CSF)45,72–74 as well as CXCL8 (IL-8).74,75 Transendothelial migration of monocytes has been described to be induced by mildly oxidized LDL attributable to endothelial CCL2 synthesis.76 Blocking of the scavenger receptor LOX-1 with antisense oligonucleotides reduces oxLDL-dependent induction of CCL2 in HAECs.44 mmLDL-induced expression of CCL2 and M-CSF by endothelial cells has been confirmed in vivo in mice.77 Conversely, lowering of lipid serum levels in rabbits results in a decrease of CCL2 production in the endothelium58 suggesting an effect of modified LDL on endothelial chemokine production.

There is strong genetic variability in endothelial responses to modified LDL as shown by differences in the level of upregulation of M-CSF, CCL2, and HO-1 by mmLDL in various inbred mouse strains.78 These findings suggest that human populations may also display various endothelial cell responses to modified LDL.

Monocytes and Macrophages
In addition to exerting effects on the endothelial cell layer, modified LDL increases monocyte recruitment to the vascular wall by directly acting on monocytes. oxLDL has long been known to contain lipids with chemotactic activity toward human monocytes.79 oxLDL and mmLDL increase monocyte CD11b expression in a PKC-dependent manner.80 Blocking of CD11a (LFA-1{alpha}), CD11b (Mac-1{alpha}), or CD18 (common ß chain) partially reduces oxLDL-induced monocyte adhesion to HUVECs under static conditions.81 In hairless mice, injection of oxLDL but not native LDL induces an increase in leukocyte interaction with the endothelium, which is reduced by blocking antibodies against the integrin CD11b/CD18.82 Oxidation of LDL generates biologically active lipids that bind to the platelet activating-factor receptor (PAFR). The role of PAFR expression on monocytes has been demonstrated in hamster experiments, where oxLDL-induced increase of leukocyte rolling is significantly attenuated when a PAFR antagonist is injected.83

Modified LDL induces expression of chemokines and chemokine receptors in monocytes and macrophages. Thus, blocking studies suggest that PAFR is crucial for oxLDL-dependent induction of CCL2 and CXCL8 in monocytes and macrophages.84 Similarly, in rabbit peritoneal macrophages oxLDL induces CCL2.85 Furthermore, oxLDL stimulates the release of CXCL8, CXCL5 (epithelial neutrophil-activating protein-78 [ENA-78]), and CXCL1 from peripheral blood mononuclear cells (PBMCs).86

In Mono-Mac-6 cells (a human cell line established from acute monoblastic leukemia exhibiting oxidative burst, phagoytotic capacities as well as expression of mature monocytic markers87), oxLDL prevents the decreased CCR2 expression induced by TNF-{alpha} and thereby restores chemotaxis of monocytes toward CCL2 and other CCR2 ligands.88 In THP-1 cells, CCR2 expression is increased after incubation with native LDL. In contrast, CCR2 is downregulated in these cells after incubation with oxLDL via a PPAR{gamma}-dependent pathway,89,90 which may represent an additional antiinflammatory effect of PPAR{gamma} agonists widely used for treating diabetes mellitus. These different effects of oxLDL may simply reflect the use of different cell lines derived from patients with monocytic leukemia, neither of which behaves like primary monocytes. In primary human monocytes, exposure of oxLDL induces CCR2 message and protein in a dose-dependent fashion.89 In blood samples of hypercholesterolemic subjects, CCR2 message is doubled versus control subjects,89 indicating that modified LDL most likely increases CCR2 expression in vivo. oxLDL also upregulates CXCR2 expression in human monocytes as well as the human monocytic cell line U937 and to thereby increase chemotaxis toward CXCL8.91

Platelets
Increasing evidence shows that platelets are involved in atherogenesis by mediating leukocyte recruitment to the endothelium. Thus, activated platelets induce expression of adhesion molecules like E-selectin, ICAM-1, and VCAM-1 and chemokines like CCL2 or CXCL8 on endothelial cells.92 Deposition of CCL5 (RANTES) and CXCL4 (PF-4) on the endothelium by activated platelets triggers arrest of monocytes.93–96 CCL5 has also been shown also be delivered to the endothelium by platelet microparticles.97

Candidate oxLDL receptors on platelets include CD3698,99 and LOX-1.100 oxLDL increases cytoplasmic calcium levels in platelets101 and amplifies platelet aggregation in response to ADP, thrombin, and other activating agents.102,103 Similar findings were reported with mmLDL.104 In vivo, hypercholesterolemia increases expression of P-selectin in platelets and enhances adhesion of platelets to the vessel wall in a P-selectin-dependent manner.105 In addition, oxLDL induces release of CXCL5 and CXCL1 (GRO-{alpha}) from platelets.86 The importance of platelets in hypercholesterolemia-induced leukocyte recruitment to the arterial wall has been demonstrated in mice, where treatment with a platelet-depleting antibody at least partially reduced leukocyte adherence to the endothelium.106 In summary, these effects of modified LDL bear the potential to increase atherosclerotic lesions by enhancing monocyte recruitment to the vessel wall.


*    Effects of Native LDL
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 up arrowIntroduction
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 *Effects of Native LDL
down arrowConclusion and Future Directions
 down arrowReferences
 
Modification of LDL substantially increases its proinflammatory effects.12,24,107 It is controversial whether native unmodified LDL plays a role in atherogenesis and monocyte recruitment to the vascular wall. The fact that native LDL may be modified during in vitro or in vivo experiments makes it challenging to determine whether any effects seen are attributable to native or at least partially modified LDL. Furthermore, native LDL can aggregate and enter the macrophage through patocytosis.11,108 Thus, aggregation of LDL may account for some of the effects seen with what is believed to be native LDL. In HUVECs in vitro as well as in the murine aortic endothelium in vivo, LDL has been shown to bind to the LDL receptor and to induce intracellular signal transduction involving activator protein-1 (AP-1).109,110

Exposure of HUVECs to LDL results in increased adherence of monocytes to the endothelium.111 Native LDL has been shown to increase adherence of monocytes to HUVECs by induction of P-selectin (only at high concentration and thus potentially an effect of traces of oxLDL)51 as well as by increased ICAM-1 expression.112 Similarly, native LDL has been demonstrated to induce VCAM-1 expression in cultured human coronary artery or pig aortic endothelial cells. Native LDL triggers a modest increase of VCAM-1 and E-selectin in human aortic endothelial cells through a rise in intracellular calcium acting as second messenger; increased VCAM-1 expression results in increased monocyte binding.113 Native LDL at physiological concentrations induces a mild increase in VCAM-1 and P-selectin expression in HACECs.114 This effect was abrogated by blocking LDL receptor, which suggests that the LDL used was native or at least only mildly modified, because LDLR does not bind oxLDL.21 Treatment of endothelial cells with a calcium chelator showed that the calcium acting as second messenger derives from intracellular calcium stores.114

In monocytes and macrophages, native LDL is bound and internalized by the LDL receptor which in contrast to scavenger receptors is downregulated by cholesterol loading.23 Native LDL has been shown to upregulate monocyte CCR2 expression in vitro and in vivo and to thereby increase chemotaxis.89 Similarly, LDL induced CD11b in human monocytes resulting in CD11b-dependent adhesion to endothelial monolayers, however only after stimulation with CCL2.115


*    Conclusion and Future Directions
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 up arrowIntroduction
 up arrowMonocyte Recruitment to the...
 up arrowNative and Modified Forms...
 up arrowEffects of Modified Forms...
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 *Conclusion and Future Directions
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LDL and especially modified forms of LDL support the development of atherosclerotic lesions not only by their effects on foam cell formation in the atherosclerotic plaques9,116 but also at earlier stages by increasing monocyte recruitment to the vessel wall. Three major mechanisms have emerged as likely contributors: (1) Modified LDL induces adhesion molecules and chemokines in endothelial cells; (2) Modified LDL has direct effects on monocytes; (3) OxLDL promotes platelet interaction with both monocytes and endothelial cells leading to more efficient monocyte recruitment. These effects enhance and accelerate the formation of atherosclerotic lesions and may cause existing lesions to become more vulnerable. The significance of different scavenger receptors for monocyte recruitment is still largely unclear. The specific components of modified LDL responsible for its increased atherogenicity remain to be identified. Models are needed to test the role of these LDL components under controlled conditions in vivo.

Therapeutically, lowering of LDL serum levels is the most valuable tool available for lowering the risk of atherosclerosis in the population at large.117 Better understanding of the mechanisms how LDL and modified forms of LDL increase monocyte recruitment to the vascular wall might result in new approaches for primary and secondary prevention.


*    Acknowledgments
 
Sources of Funding

This work was supported by the Deutsche Forschungsgemeinschaft (grant GL599/1-1 to C.A.G.) and by National Institutes of Health grant HL58108 (to K.L.).

Disclosures

None.

Received February 22, 2007; first decision March 19, 2007; accepted May 7, 2007.


*    References
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  1. Ross R. Atherosclerosis is an inflammatory disease. Am Heart J. 1999; 138: S419–420.[CrossRef][Medline] [Order article via Infotrieve]
  2. Libby P. Inflammation in atherosclerosis. Nature. 2002; 420: 868–874.[CrossRef][Medline] [Order article via Infotrieve]
  3. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352: 1685–1695.[Free Full Text]
  4. Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: global burden of disease study. Lancet. 1997; 349: 1436–1442.[CrossRef][Medline] [Order article via Infotrieve]
  5. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006; 3: e442.[CrossRef][Medline] [Order article via Infotrieve]
  6. Osterud B, Bjorklid E. Role of monocytes in atherogenesis. Physiol Rev. 2003; 83: 1069–1112.[Abstract/Free Full Text]
  7. Shashkin P, Dragulev B, Ley K. Macrophage differentiation to foam cells. Curr Pharm Des. 2005; 11: 3061–3072.[CrossRef][Medline] [Order article via Infotrieve]
  8. Bobryshev YV. Dendritic cells in atherosclerosis: current status of the problem and clinical relevance. Eur Heart J. 2005; 26: 1700–1704.[Abstract/Free Full Text]
  9. Tabas I. Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency. Arterioscler Thromb Vasc Biol. 2005; 25: 2255–2264.[Abstract/Free Full Text]
  10. Chisolm GM, Steinberg D. The oxidative modification hypothesis of atherogenesis: an overview. Free Radic Biol Med. 2000; 28: 1815–1826.[CrossRef][Medline] [Order article via Infotrieve]
  11. Oorni K, Pentikainen MO, Ala-Korpela M, Kovanen PT. Aggregation, fusion, and vesicle formation of modified low density lipoprotein particles: molecular mechanisms and effects on matrix interactions. J Lipid Res. 2000; 41: 1703–1714.[Abstract/Free Full Text]
  12. Miller YI, Chang MK, Binder CJ, Shaw PX, Witztum JL. Oxidized low density lipoprotein and innate immune receptors. Curr Opin Lipidol. 2003; 14: 437–445.[CrossRef][Medline] [Order article via Infotrieve]
  13. Tabas I. Nonoxidative modifications of lipoproteins in atherogenesis. Annu Rev Nutr. 1999; 19: 123–139.[CrossRef][Medline] [Order article via Infotrieve]
  14. Bobryshev YV. Monocyte recruitment and foam cell formation in atherosclerosis. Micron. 2006; 37: 208–222.[CrossRef][Medline] [Order article via Infotrieve]
  15. Eriksson EE. Mechanisms of leukocyte recruitment to atherosclerotic lesions: future prospects. Curr Opin Lipidol. 2004; 15: 553–558.[CrossRef][Medline] [Order article via Infotrieve]
  16. Quehenberger O. Thematic review series: the immune system and atherogenesis. Molecular mechanisms regulating monocyte recruitment in atherosclerosis. J Lipid Res. 2005; 46: 1582–1590.[Abstract/Free Full Text]
  17. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994; 76: 301–314.[CrossRef][Medline] [Order article via Infotrieve]
  18. Huo Y, Ley K. Adhesion molecules and atherogenesis. Acta Physiol Scand. 2001; 173: 35–43.[CrossRef][Medline] [Order article via Infotrieve]
  19. Weber C, Schober A, Zernecke A. Chemokines: key regulators of mononuclear cell recruitment in atherosclerotic vascular disease. Arterioscler Thromb Vasc Biol. 2004; 24: 1997–2008.[Abstract/Free Full Text]
  20. Smith LC, Pownall HJ, Gotto AM Jr. The plasma lipoproteins: structure and metabolism. Annu Rev Biochem. 1978; 47: 751–757.[CrossRef][Medline] [Order article via Infotrieve]
  21. Jeon H, Blacklow SC. Structure and physiologic function of the low-density lipoprotein receptor. Annu Rev Biochem. 2005; 74: 535–562.[CrossRef][Medline] [Order article via Infotrieve]
  22. Hiltunen TP, Yla-Herttuala S. Expression of lipoprotein receptors in atherosclerotic lesions. Atherosclerosis. 1998; 137 (Suppl): S81–S88.[CrossRef][Medline] [Order article via Infotrieve]
  23. Howell BW, Herz J. The LDL receptor gene family: signaling functions during development. Curr Opin Neurobiol. 2001; 11: 74–81.[CrossRef][Medline] [Order article via Infotrieve]
  24. Steinberg D. Low density lipoprotein oxidation and its pathobiological significance. J Biol Chem. 1997; 272: 20963–20966.[Free Full Text]
  25. Takahashi Y, Zhu H, Yoshimoto T. Essential roles of lipoxygenases in LDL oxidation and development of atherosclerosis. Antioxidants & Redox Signaling. 2005; 7: 425–431.[CrossRef][Medline] [Order article via Infotrieve]
  26. Yla-Herttuala S, Palinski W, Rosenfeld ME, Parthasarathy S, Carew TE, Butler S, Witztum JL, Steinberg D. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest. 1989; 84: 1086–1095.[Medline] [Order article via Infotrieve]
  27. Torzewski M, Lackner KJ. Initiation and progression of atherosclerosis-enzymatic or oxidative modification of low-density lipoprotein? Clin Chem Lab Med. 2006; 44: 1389–1394.[CrossRef][Medline] [Order article via Infotrieve]
  28. Torzewski M, Klouche M, Hock J, Messner M, Dorweiler B, Torzewski J, Gabbert HE, Bhakdi S. Immunohistochemical demonstration of enzymatically modified human LDL and its colocalization with the terminal complement complex in the early atherosclerotic lesion. Arterioscler Thromb Vasc Biol. 1998; 18: 369–378.[Abstract/Free Full Text]
  29. Saad AF, Virella G, Chassereau C, Boackle RJ, Lopes-Virella MF. OxLDL immune complexes activate complement and induce cytokine production by monomac 6 cells and human macrophages. J Lipid Res. 2006; 47: 1975–1983.[Abstract/Free Full Text]
  30. Matsuura E, Kobayashi K, Tabuchi M, Lopez LR. Oxidative modification of low-density lipoprotein and immune regulation of atherosclerosis. Prog Lipid Res. 2006; 45: 466–486.[CrossRef][Medline] [Order article via Infotrieve]
  31. Moore KJ, Freeman MW. Scavenger receptors in atherosclerosis: Beyond lipid uptake. Arterioscler Thromb Vasc Biol. 2006; 26: 1702–1711.[Abstract/Free Full Text]
  32. Suzuki H, Kurihara Y, Takeya M, Kamada N, Kataoka M, Jishage K, Ueda O, Sakaguchi H, Higashi T, Suzuki T, Takashima Y, Kawabe Y, Cynshi O, Wada Y, Honda M, Kurihara H, Aburatani H, Doi T, Matsumoto A, Azuma S, Noda T, Toyoda Y, Itakura H, Yazaki Y, Horiuchi S, Takahashi K, Kruijt JK, van Berkel TJC, Steinbrecher UP, Ishibashi S, Maeda N, Gordon S, Kodama T. A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection. Nature. 1997; 386: 292–296.[CrossRef][Medline] [Order article via Infotrieve]
  33. Febbraio M, Podrez EA, Smith JD, Hajjar DP, Hazen SL, Hoff HF, Sharma K, Silverstein RL. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. J Clin Invest. 2000; 105: 1049–1056.[Medline] [Order article via Infotrieve]
  34. Kunjathoor VV, Febbraio M, Podrez EA, Moore KJ, Andersson L, Koehn S, Rhee JS, Silverstein R, Hoff HF, Freeman MW. Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J Biol Chem. 2002; 277: 49982–49988.[Abstract/Free Full Text]
  35. Yoshida H, Quehenberger O, Kondratenko N, Green S, Steinberg D. Minimally oxidized low-density lipoprotein increases expression of scavenger receptor A, CD36, and macrosialin in resident mouse peritoneal macrophages. Arterioscler Thromb Vasc Biol. 1998; 18: 794–802.[Abstract/Free Full Text]
  36. Oka K, Sawamura T, Kikuta K, Itokawa S, Kume N, Kita T, Masaki T. Lectin-like oxidized low-density lipoprotein receptor 1 mediates phagocytosis of aged/apoptotic cells in endothelial cells. Proc Natl Acad Sci U S A. 1998; 95: 9535–9540.[Abstract/Free Full Text]
  37. Shimaoka T, Kume N, Minami M, Hayashida K, Kataoka H, Kita T, Yonehara S. Molecular cloning of a novel scavenger receptor for oxidized low density lipoprotein, SR-PSOX, on macrophages. J Biol Chem. 2000; 275: 40663–40666.[Abstract/Free Full Text]
  38. de Villiers W, Smart E. Macrophage scavenger receptors and foam cell formation. J Leukoc Biol. 1999; 66: 740–746.[Abstract]
  39. Frostegard J, Nilsson J, Haegerstrand A, Hamsten A, Wigzell H, Gidlund M. Oxidized low density lipoprotein induces differentiation and adhesion of human monocytes and the monocytic cell line U937. Proc Natl Acad Sci U S A. 1990; 87: 904–908.[Abstract/Free Full Text]
  40. Berliner JA, Territo MC, Sevanian A, Ramin S, Kim JA, Bamshad B, Esterson M, Fogelman AM. Minimally modified low density lipoprotein stimulates monocyte endothelial interactions. J Clin Invest. 1990; 85: 1260–1266.[Medline] [Order article via Infotrieve]
  41. Lehr HA, Hubner C, Finckh B, Angermuller S, Nolte D, Beisiegel U, Kohlschutter A, Messmer K. Role of leukotrienes in leukocyte adhesion following systemic administration of oxidatively modified human low density lipoprotein in hamsters. J Clin Invest. 1991; 88: 9–14.[Medline] [Order article via Infotrieve]
  42. Napoli C, D’Armiento FP, Mancini FP, Postiglione A, Witztum JL, Palumbo G, Palinski W. Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J Clin Invest. 1997; 100: 2680–2690.[Medline] [Order article via Infotrieve]
  43. Kopprasch S, Pietzsch J, Westendorf T, Kruse HJ, Grassler J. The pivotal role of scavenger receptor CD36 and phagocyte-derived oxidants in oxidized low density lipoprotein-induced adhesion to endothelial cells. Int J Biochem Cell Biol. 2004; 36: 460–471.[CrossRef][Medline] [Order article via Infotrieve]
  44. Li D, Mehta JL. Antisense to LOX-1 inhibits oxidized LDL-mediated upregulation of monocyte chemoattractant protein-1 and monocyte adhesion to human coronary artery endothelial cells. Circulation. 2000; 101: 2889–2895.[Abstract/Free Full Text]
  45. Parhami F, Fang ZT, Fogelman AM, Andalibi A, Territo MC, Berliner JA. Minimally modified low density lipoprotein-induced inflammatory responses in endothelial cells are mediated by cyclic adenosine monophosphate. J Clin Invest. 1993; 92: 471–478.[Medline] [Order article via Infotrieve]
  46. Rajavashisth TB, Yamada H, Mishra NK. Transcriptional activation of the macrophage-colony stimulating factor gene by minimally modified LDL: Involvement of nuclear factor-{kappa}B. Arterioscler Thromb Vasc Biol. 1995; 15: 1591–1598.[Abstract/Free Full Text]
  47. Peng HB, Rajavashisth TB, Libby P, Liao JK. Nitric oxide inhibits macrophage-colony stimulating factor gene transcription in vascular endothelial cells. J Biol Chem. 1995; 270: 17050–17055.[Abstract/Free Full Text]
  48. Tsao PS, Buitrago R, Chan JR, Cooke JP. Fluid flow inhibits endothelial adhesiveness. Nitric oxide and transcriptional regulation of VCAM-1. Circulation. 1996; 94: 1682–1689.[Abstract/Free Full Text]
  49. Kawakami A, Aikawa M, Alcaide P, Luscinskas FW, Libby P, Sacks FM. Apolipoprotein CIII induces expression of vascular cell adhesion molecule-1 in vascular endothelial cells and increases adhesion of monocytic cells. Circulation. 2006; 114: 681–687.[Abstract/Free Full Text]
  50. Honda HM, Leitinger N, Frankel M, Goldhaber JI, Natarajan R, Nadler JL, Weiss JN, Berliner JA. Induction of monocyte binding to endothelial cells by mm-LDL: role of lipoxygenase metabolites. Arterioscler Thromb Vasc Biol. 1999; 19: 680–686.[Abstract/Free Full Text]
  51. Gebuhrer V, Murphy JF, Bordet JC, Reck MP, McGregor JL. Oxidized low-density lipoprotein induces the expression of P-selectin (GMP140 / PADGEM / CD62) on human endothelial cells. Biochem J. 1995; 306 (Pt1): 293–298.[Medline] [Order article via Infotrieve]
  52. Vora DK, Fang ZT, Liva SM, Tyner TR, Parhami F, Watson AD, Drake TA, Territo MC, Berliner JA. Induction of P-selectin by oxidized lipoproteins. Separate effects on synthesis and surface expression. Circ Res. 1997; 80: 810–818.[Abstract/Free Full Text]
  53. Chen H, Li D, Saldeen T, Mehta JL. Transforming growth factor-ß1 modulates oxidatively modified LDL-induced expression of adhesion molecules: Role of LOX-1. Circ Res. 2001; 89: 1155–1160.[Abstract/Free Full Text]
  54. Khan BV, Parthasarathy SS, Alexander RW, Medford RM. Modified low density lipoprotein and its constituents augment cytokine-activated vascular cell adhesion molecule-1 gene expression in human vascular endothelial cells. J Clin Invest. 1995; 95: 1262–1270.[Medline] [Order article via Infotrieve]
  55. Shigeru Tsuchiya MY, Yoshiko Yamaguchi, Yasuko Kobayashi, Tasuke Konno, Keiya Tada. Establishment and characterization of a human acute monocytic leukemia cell line (THP-1). Int J Cancer. 1980; 26: 171–176.[Medline] [Order article via Infotrieve]
  56. Li H, Cybulsky MI, Gimbrone MA Jr, Libby P. An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium. Arterioscler Thromb. 1993; 13: 197–204.[Abstract/Free Full Text]
  57. Calara F, Dimayuga P, Niemann A, Thyberg J, Diczfalusy U, Witztum JL, Palinski W, Shah PK, Cercek B, Nilsson J, Regnstrom J. An animal model to study local oxidation of LDL and its biological effects in the arterial wall. Arterioscler Thromb Vasc Biol. 1998; 18: 884–893.[Abstract/Free Full Text]
  58. Aikawa M, Sugiyama S, Hill CC, Voglic SJ, Rabkin E, Fukumoto Y, Schoen FJ, Witztum JL, Libby P. Lipid lowering reduces oxidative stress and endothelial cell activation in rabbit atheroma. Circulation. 2002; 106: 1390–1396.[Abstract/Free Full Text]
  59. Quinn MT, Parthasarathy S, Steinberg D. Lysophosphatidylcholine: A chemotactic factor for human monocytes and its potential role in atherogenesis. Proc Natl Acad Sci U S A. 1988; 85: 2805–2809.[Abstract/Free Full Text]
  60. Sundstrom C, Nilsson K. Establishment and characterization of a human histiocytic lymphoma cell line (U-937). Int J Cancer. 1976; 17: 565–577.[Medline] [Order article via Infotrieve]
  61. Kume N, Cybulsky MI, Gimbrone MA Jr. Lysophosphatidylcholine, a component of atherogenic lipoproteins, induces mononuclear leukocyte adhesion molecules in cultured human and rabbit arterial endothelial cells. J Clin Invest. 1992; 90: 1138–1144.[Medline] [Order article via Infotrieve]
  62. Karabina S-A, Brocheriou I, Le Naour G, Agrapart M, Durand H, Gelb M, Lambeau G, Ninio E. Atherogenic properties of LDL particles modified by human group x secreted phospholipase A2 on human endothelial cell function. Faseb J. 2006; 20: 2547–2549.[Abstract/Free Full Text]
  63. Klouche M, May AE, Hemmes M, Messner M, Kanse SM, Preissner KT, Bhakdi S. Enzymatically modified, nonoxidized LDL induces selective adhesion and transmigration of monocytes and T-lymphocytes through human endothelial cell monolayers. Arterioscler Thromb Vasc Biol. 1999; 19: 784–793.[Abstract/Free Full Text]
  64. Shih PT, Elices MJ, Fang ZT, Ugarova TP, Strahl D, Territo MC, Frank JS, Kovach NL, Cabanas C, Berliner JA, Vora DK. Minimally modified low-density lipoprotein induces monocyte adhesion to endothelial connecting segment-1 by activating ß1 integrin. J Clin Invest. 1999; 103: 613–625.[Medline] [Order article via Infotrieve]
  65. Keiper T, Al-Fakhri N, Chavakis E, Athanasopoulos AN, Isermann B, Herzog S, Saffrich R, Hersemeyer K, Bohle RM, Haendeler J, Preissner KT, Santoso S, Chavakis T. The role of junctional adhesion molecule-c (JAM-C) in oxidized LDL-mediated leukocyte recruitment. Faseb J. 2005; 19: 2078–2080.[Abstract/Free Full Text]
  66. Ishikawa K, Navab M, Leitinger N, Fogelman AM, Lusis AJ. Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL. J Clin Invest. 1997; 100: 1209–1216.[Medline] [Order article via Infotrieve]
  67. Wang LJ, Lee TS, Lee FY, Pai RC, Chau LY. Expression of heme oxygenase-1 in atherosclerotic lesions. Am J Pathol. 1998; 152: 711–720.[Abstract]
  68. Stocker R, Perrella MA. Heme oxygenase-1: a novel drug target for atherosclerotic diseases? Circulation. 2006; 114: 2178–2189.[Free Full Text]
  69. Sotiriou SN, Orlova VV, Al-Fakhri N, Ihanus E, Economopoulou M, Isermann B, Bdeir K, Nawroth PP, Preissner KT, Gahmberg CG, Koschinsky ML, Chavakis T Lipoprotein(a) in atherosclerotic plaques recruits inflammatory cells through interaction with Mac-1 integrin. Faseb J. 2006: 05–4857fje.
  70. McMurray HF, Parthasarathy S, Steinberg D. Oxidatively modified low density lipoprotein is a chemoattractant for human T lymphocytes. J Clin Invest. 1993; 92: 1004–1008.[Medline] [Order article via Infotrieve]
  71. Quinn MT, Parthasarathy S, Fong LG, Steinberg D. Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc Natl Acad Sci U S A. 1987; 84: 2995–2998.[Abstract/Free Full Text]
  72. Cushing SD, Berliner JA, Valente AJ, Territo MC, Navab M, Parhami F, Gerrity R, Schwartz CJ, Fogelman AM. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc Natl Acad Sci U S A. 1990; 87: 5134–5138.[Abstract/Free Full Text]
  73. Rajavashisth TB, Andalibi A, Territo MC, Berliner JA, Navab M, Fogelman AM, Lusis AJ. Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins. Nature. 1990; 344: 254–257.[CrossRef][Medline] [Order article via Infotrieve]
  74. Lee H, Shi W, Tontonoz P, Wang S, Subbanagounder G, Hedrick CC, Hama S, Borromeo C, Evans RM, Berliner JA, Nagy L. Role for peroxisome proliferator-activated receptor {alpha} in oxidized phospholipid-induced synthesis of monocyte chemotactic protein-1 and interleukin-8 by endothelial cells. Circ Res. 2000; 87: 516–521.[Abstract/Free Full Text]
  75. Suriyaphol P, Fenske D, Zahringer U, Han SR, Bhakdi S, Husmann M. Enzymatically modified nonoxidized low-density lipoprotein induces interleukin-8 in human endothelial cells: role of free fatty acids. Circulation. 2002; 106: 2581–2587.[Abstract/Free Full Text]
  76. Navab M, Imes SS, Hama SY, Hough GP, Ross LA, Bork RW, Valente AJ, Berliner JA, Drinkwater DC, Laks H. Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein. J Clin Invest. 1991; 88: 2039–2046.[Medline] [Order article via Infotrieve]
  77. Liao F, Berliner JA, Mehrabian M, Navab M, Demer LL, Lusis AJ, Fogelman AM. Minimally modified low density lipoprotein is biologically active in vivo in mice. J Clin Invest. 1991; 87: 2253–2257.[Medline] [Order article via Infotrieve]
  78. Shi W, Haberland ME, Jien M-L, Shih DM, Lusis AJ. Endothelial responses to oxidized lipoproteins determine genetic susceptibility to atherosclerosis in mice. Circulation. 2000; 102: 75–81.[Abstract/Free Full Text]
  79. Quinn MT, Parthasarathy S, Steinberg D. Endothelial cell-derived chemotactic activity for mouse peritoneal macrophages and the effects of modified forms of low density lipoprotein. Proc Natl Acad Sci U S A. 1985; 82: 5949–5953.[Abstract/Free Full Text]
  80. Weber C, Erl W, Weber PC. Enhancement of monocyte adhesion to endothelial cells by oxidatively modified low-density lipoprotein is mediated by activation of cd11b. Biochem Biophys Res Commun. 1995; 206: 621–628.[CrossRef][Medline] [Order article via Infotrieve]
  81. Mine S, Tabata T, Wada Y, Fujisaki T, Iida T, Noguchi N, Niki E, Kodama T, Tanaka Y. Oxidized low density lipoprotein-induced LFA-1-dependent adhesion and transendothelial migration of monocytes via the protein kinase C pathway. Atherosclerosis. 2002; 160: 281–288.[CrossRef][Medline] [Order article via Infotrieve]
  82. Lehr HA, Krober M, Hubner C, Vajkoczy P, Menger MD, Nolte D, Kohlschutter A, Messmer K. Stimulation of leukocyte/endothelium interaction by oxidized low-density lipoprotein in hairless mice. Involvement of CD11b/CD18 adhesion receptor complex. Lab Invest. 1993; 68: 388–395.[Medline] [Order article via Infotrieve]
  83. Lehr HA, Seemuller J, Hubner C, Menger MD, Messmer K. Oxidized LDL-induced leukocyte/endothelium interaction in vivo involves the receptor for platelet-activating factor. Arterioscler Thromb. 1993; 13: 1013–1018.[Abstract/Free Full Text]
  84. Beaudeux JL, Said T, Ninio E, Ganne F, Soria J, Delattre J, Soria C, Legrand A, Peynet J. Activation of PAF receptor by oxidised LDL in human monocytes stimulates chemokine releases but not urokinase-type plasminogen activator expression. Clin Chim Acta. 2004; 344: 163–171.[CrossRef][Medline] [Order article via Infotrieve]
  85. Wang GP, Deng ZD, Ni J, Qu ZL. Oxidized low density lipoprotein and very low density lipoprotein enhance expression of monocyte chemoattractant protein-1 in rabbit peritoneal exudate macrophages. Atherosclerosis. 1997; 133: 31–36.[CrossRef][Medline] [Order article via Infotrieve]
  86. Holm T, Damas JK, Holven K, Nordoy I, Brosstad FR, Ueland T, Wahre T, Kjekshus J, Froland SS, Eiken HG, Solum NO, Gullestad L, Nenseter M, Aukrust P. CXC-chemokines in coronary artery disease: possible pathogenic role of interactions between oxidized low-density lipoprotein, platelets and peripheral blood mononuclear cells. J Thromb Haemost. 2003; 1: 257–262.[CrossRef][Medline] [Order article via Infotrieve]
  87. Ziegler-Heitbrock L, Thiel E, Futterer A, Herzog V, Wirtz A, Riethmüller G. Establishment of a human cell line (mono mac 6) with characteristics of mature monocytes. Int J Cancer. 1988; 41: 456–461.[Medline] [Order article via Infotrieve]
  88. Weber C, Draude G, Weber KSC, Wubert J, Lorenz RL, Weber PC. Downregulation by tumor necrosis factor-{alpha} of monocyte CCR2 expression and monocyte chemotactic protein-1-induced transendothelial migration is antagonized by oxidized low-density lipoprotein: a potential mechanism of monocyte retention in atherosclerotic lesions. Atherosclerosis. 1999; 145: 115–123.[CrossRef][Medline] [Order article via Infotrieve]
  89. Han KH, Tangirala RK, Green SR, Quehenberger O. Chemokine receptor CCR2 expression and monocyte chemoattractant protein-1–mediated chemotaxis in human monocytes: a regulatory role for plasma LDL. Arterioscler Thromb Vasc Biol. 1998; 18: 1983–1991.[Abstract/Free Full Text]
  90. Han KH, Chang MK, Boullier A, Green SR, Li A, Glass CK, Quehenberger O. Oxidized LDL reduces monocyte CCR2 expression through pathways involving peroxisome proliferator-activated receptor {gamma}. J Clin Invest. 2000; 106: 793–802.[Medline] [Order article via Infotrieve]
  91. Lei Z-B, Zhang Z, Jing Q, Qin Y-W, Pei G, Cao B-Z, Li X-Y. OxLDL upregulates CXCR2 expression in monocytes via scavenger receptors and activation of p38 mitogen-activated protein kinase. Cardiovasc Res. 2002; 53: 524–532.[Abstract/Free Full Text]
  92. Gawaz M, Neumann FJ, Dickfeld T, Koch W, Laugwitz KL, Adelsberger H, Langenbrink K, Page S, Neumeier D, Schomig A, Brand K. Activated platelets induce monocyte chemotactic protein-1 secretion and surface expression of intercellular adhesion molecule-1 on endothelial cells. Circulation. 1998; 98: 1164–1171.[Abstract/Free Full Text]
  93. Massberg S, Brand K, Gruner S, Page S, Muller E, Muller I, Bergmeier W, Richter T, Lorenz M, Konrad I, Nieswandt B, Gawaz M. A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp Med. 2002; 196: 887–896.[Abstract/Free Full Text]
  94. Huo Y, Schober A, Forlow SB, Smith DF, Hyman MC, Jung S, Littman DR, Weber C, Ley K. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med. 2003; 9: 61–67.[CrossRef][Medline] [Order article via Infotrieve]
  95. von Hundelshausen P, Weber KS, Huo Y, Proudfoot AE, Nelson PJ, Ley K, Weber C. RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation. 2001; 103: 1772–1777.[Abstract/Free Full Text]
  96. Schober A, Manka D, von Hundelshausen P, Huo Y, Hanrath P, Sarembock IJ, Ley K, Weber C. Deposition of platelet RANTES triggering monocyte recruitment requires P-selectin and is involved in neointima formation after arterial injury. Circulation. 2002; 106: 1523–1529.[Abstract/Free Full Text]
  97. Mause SF, von Hundelshausen P, Zernecke A, Koenen RR, Weber C. Platelet microparticles: A transcellular delivery system for RANTES promoting monocyte recruitment on endothelium. Arterioscler Thromb Vasc Biol. 2005; 25: 1512–1518.[Abstract/Free Full Text]
  98. Volf I, Moeslinger T, Cooper J, Schmid W, Koller E. Human platelets exclusively bind oxidized low density lipoprotein showing no specificity for acetylated low density lipoprotein. FEBS Lett. 1999; 449: 141–145.[CrossRef][Medline] [Order article via Infotrieve]
  99. Endemann G, Stanton L, Madden K, Bryant C, White R, Protter A. CD36 is a receptor for oxidized low density lipoprotein. J Biol Chem. 1993; 268: 11811–11816.[Abstract/Free Full Text]
  100. Chen M, Kakutani M, Naruko T, Ueda M, Narumiya S, Masaki T, Sawamura T. Activation-dependent surface expression of LOX-1 in human platelets. Biochem Biophys Res Commun. 2001; 282: 153–158.[CrossRef][Medline] [Order article via Infotrieve]
  101. Zhao B, Dierichs R, Miller FN, Dean WL. Oxidized low density lipoprotein inhibits platelet plasma membrane Ca(2+)-ATPase. Cell Calcium. 1996; 19: 453–458.[CrossRef][Medline] [Order article via Infotrieve]
  102. Zhao B, Rickert CH, Filler TJ, Liu B, Verhallen PF, Dierichs R. Adhesion of washed blood platelets in vitro is advanced, accelerated, and enlarged by oxidized low-density lipoprotein. Am J Hematol. 1995; 49: 177–182.[Medline] [Order article via Infotrieve]
  103. Coleman LG Jr, Polanowska-Grabowska RK, Marcinkiewicz M, Gear ARL. LDL oxidized by hypochlorous acid causes irreversible platelet aggregation when combined with low levels of adp, thrombin, epinephrine, or macrophage-derived chemokine (CCL22). Blood. 2004; 104: 380–389.[Abstract/Free Full Text]
  104. Weidtmann A, Scheithe R, Hrboticky N, Pietsch A, Lorenz R, Siess W. Mildly oxidized LDL induces platelet aggregation through activation of phospholipase A2. Arterioscler Thromb Vasc Biol. 1995; 15: 1131–1138.[Abstract/Free Full Text]
  105. Tailor A, Granger DN. Hypercholesterolemia promotes P-selectin-dependent platelet-endothelial cell adhesion in postcapillary venules. Arterioscler Thromb Vasc Biol. 2003; 23: 675–680.[Abstract/Free Full Text]
  106. Stokes KY, Calahan L, Russell JM, Gurwara S, Granger DN. Role of platelets in hypercholesterolemia-induced leukocyte recruitment and arteriolar dysfunction. Microcirculation. 2006; 13: 377–388.