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

Coleman, Leon G.; Polanowska-Grabowska, Renata; Marcinkiewicz, M.; Gear, Adrian R.L.

doi:10.1182/blood-2003-08-2961

Cited by 29 publications

(24 citation statements)

References 100 publications

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“…100 oxLDL increases cytoplasmic calcium levels in platelets 101 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.…”

Section: Plateletssupporting

confidence: 83%

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

2007

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Section: Plateletssupporting

confidence: 83%

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

2007

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“…[41][42][43][44] Our data clearly identify a central role for the interaction of CD36 with specific oxidized phospholipids within oxLDL in platelet signaling. CD36-specific ligands are generated when LDL is oxidized in vitro and in vivo and have been shown to accumulate in atherosclerotic plaque and to circulate in the blood of patients with hyperlipidemia and atherosclerosis.…”

Section: Discussionmentioning

confidence: 62%

“…Our studies (data not shown) and those of others have shown that another member of the MAP kinase family, p38, is phosphorylated in platelets after exposure to oxLDL. 33,41,42 Whether p38 and JNK work synergistically or independently in the process of platelet activation by oxLDL remains to be determined. The precise function of JNK in platelet biology also remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

A Specific CD36-Dependent Signaling Pathway Is Required for Platelet Activation by Oxidized Low-Density Lipoprotein

Chen

Febbraio

et al. 2008

Circulation Research

164

181

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Abstract-Platelet hyperactivity associated with hyperlipidemia may contribute to development of a prothrombotic state.We previously showed that oxidized low-density lipoprotein (oxLDL) formed in the setting of hyperlipidemia and atherosclerosis activated platelets in a CD36-dependent manner. We now show that mitogen-activated protein kinase c-Jun N-terminal kinase (JNK)2 and its upstream activator MKK4 were phosphorylated in platelets exposed to oxLDL. Using apoE Ϫ/Ϫ mice as a model of hyperlipidemia, we showed that JNK was constitutively phosphorylated in platelets in a CD36-dependent manner. Inhibition of src kinase activity reduced JNK phosphorylation by oxLDL. Immunoprecipitations revealed that active phosphorylated forms of src kinases Fyn and Lyn were recruited to CD36 in platelets exposed to oxLDL. Pharmacological inhibition of the mitogen-activated protein kinase JNK or src family kinases abolished platelet activation by oxLDL in vitro. Using a murine carotid artery thrombosis model we demonstrated CD36-dependent phosphorylation of platelet JNK within thrombi. Furthermore, pharmacological inhibition of JNK prolonged thrombosis times in wild-type but not cd36-null mice in vivo. These findings suggest that a specific CD36-dependent signaling pathway is required for platelet activation by oxLDL and may provide insights related to development of novel antiplatelet therapies more relevant to atherothrombosis than to normal hemostasis. (Circ Res. 2008;102:1512-1519.)Key Words: CD36 Ⅲ JNK Ⅲ thrombosis Ⅲ hyperlipidemia C D36 is an integral membrane protein expressed on monocytes/macrophages, 1 platelets, 2 microvascular endothelium, 1 fat, and muscle. 3,4 Although initially identified as a receptor for thrombospondin-1 and malaria-infected erythrocytes, 5,6 it is now known to be a class B scavenger receptor that recognizes several unrelated ligands, including thrombospondin-1 and -2, 7,8 oxidized phospholipids expressed on oxidized low-density lipoprotein (oxLDL) and apoptotic cell surfaces, 9,10 long chain fatty acids, 11 amyloidogenic peptides, 12 and specific components of microbial cell walls or cell surfaces. 13 CD36 is involved in a variety of biological processes including lipid metabolism, inflammation, atherosclerosis, and angiogenesis, depending on the nature of the ligand to which it is exposed and the cell or tissue type on which it is expressed. 14 Although CD36 was first isolated and structurally characterized from platelets, 2 its functional role on platelets remains incompletely characterized. OKM5, a monoclonal antibody directed against CD36, was observed many years ago to induce platelet activation and aggregation. 15 Although the effect was dependent on expression of Fc receptors, it could be blocked by F(abЈ) 2 fragments of the antibody, suggesting that the CD36 epitope was required and that CD36 may transduce platelet activating signals. Many other CD36 monoclonal antibodies have also been shown to have stimulatory effects on platelets. 16 Our group in collaboration with others recently sho...

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“…21,22 Because monocytes constitutively express P-selectin glycoprotein ligand-1 (PSGL-1), OxLDL-stimulated platelets also interacted with monocytes within minutes of activation ( Figure 1A). As depicted in Figure 1B, the percentage of platelet-monocyte complexes significantly increased with the degree of oxidative modification of LDL, whereas native LDL had no effect on PMA formation.…”

Section: In Response To Oxldl Platelets Rapidly Formed Complexes Withmentioning

confidence: 99%

Platelets Mediate Oxidized Low-Density Lipoprotein–Induced Monocyte Extravasation and Foam Cell Formation

Badrnya

Schrottmaier

Kral

et al. 2014

ATVB

139

115

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Objective-A growing body of evidence indicates that platelets contribute to the onset and progression of atherosclerosis by modulating immune responses. We aimed to elucidate the effects of oxidized low-density lipoprotein (OxLDL) on platelet-monocyte interactions and the consequences of these interactions on platelet phagocytosis, chemokine release, monocyte extravasation, and foam cell formation. Approach and Results-Confocal microscopy and flow cytometric analysis revealed that in vitro and in vivo stimulation with OxLDL resulted in rapid formation of platelet-monocyte aggregates, with a preference for CD16+ monocyte subsets. This platelet-monocyte interaction facilitated OxLDL uptake by monocytes, in a process that involved platelet CD36-OxLDL interaction, release of chemokines, such as CXC motif ligand 4, direct platelet-monocyte interaction, and phagocytosis of platelets. Inhibition of cyclooxygenase with acetylsalicylic acid and antagonists of ADP receptors, P2Y1 and P2Y12, partly abrogated OxLDL-induced platelet-monocyte aggregates and platelet-mediated lipid uptake in monocytes. Platelets also enhanced OxLDL-induced monocyte transmigration across an endothelial monolayer via direct interaction with monocytes in a transwell assay. Importantly, in LDLR −/− mice, platelet depletion resulted in a significant decrease of peritoneal macrophage recruitment and foam cell formation in a thioglycollate-elicited peritonitis model. In platelet-depleted wild-type mice, transfusion of ex vivo OxLDL-stimulated platelets induced monocyte extravasation to a higher extent when compared with resting platelets. Conclusions-Our results on OxLDL-mediated platelet-monocyte aggregate formation, which promoted phenotypic changes in monocytes, monocyte extravasation and enhanced foam cell formation in vitro and in vivo, provide a novel mechanism for how platelets potentiate key steps of atherosclerotic plaque development and plaque destabilization.

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

Cited by 29 publications

References 100 publications

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

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

A Specific CD36-Dependent Signaling Pathway Is Required for Platelet Activation by Oxidized Low-Density Lipoprotein

Platelets Mediate Oxidized Low-Density Lipoprotein–Induced Monocyte Extravasation and Foam Cell Formation

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