scholarly journals Prothrombotic Platelet Signaling by the Scavenger Receptor, CD36.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3642-3642
Author(s):  
Kan Chen ◽  
Maria Febbraio ◽  
Roy Silverstein
Keyword(s):  
Platelet Activation ◽  
Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Low Density Lipoprotein ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Adenosine Diphosphate ◽  
Mapk Signaling ◽  
Signaling Cascade

Abstract The scavenger receptor CD36 binds a broad array of ligands, including oxidized low density lipoprotein (oxLDL), thrombospondin-1, fatty acids and apoptotic cells. CD36 was first isolated and characterized structurally from platelets, but the functional role of CD36 on platelets remains relatively obscure. We previously determined that treating platelets with oxLDL activated platelets and that activation was not seen in CD36-null platelets. Using a pharmacological inhibitor we now show that inhibition of JNK MAP kinase abrogated the activation of platelets by oxLDL. This effect was specific to oxLDL-mediated activation because this inhibitor had minimal effect on platelet activation by other classic agonists as exemplified by adenosine diphosphate (ADP). We demonstrated by immunoblotting that JNK2 and its upstream activator MKK4 were phosphorylated in the presence of oxLDL. We also found that the increase of JNK2 phosphorylation by oxLDL was diminished in CD36-null platelets. We showed that a src family kinase inhibitor (AG1879) blocked both platelet activation and JNK2 phosphorylation upon oxLDL treatment. By co-immunoprecipitation we demonstrated that CD36 recruited “active” fyn and lyn in platlets upon oxLDL treatment. These studies suggest that CD36 ligands can activate platelets through a signaling cascade involving src family tyrosine kinases and MAPK signaling molecules such as MKK4 and JNK2. OxLDL forms in the setting of hyperlipidemia and inflammation and plays an important role in atherosclerosis. A common characteristic of atherosclerosis is a prothrombotic state. Our results suggested that a specific signaling cascade activated by CD36 ligands generated in pathological states may contribute to a prothrombotic phenotype in vivo.

scholarly journals Platelet CD36 signaling through ERK5 promotes caspase-dependent procoagulant activity and fibrin deposition in vivo

2018 ◽  
Vol 2 (21) ◽  
pp. 2848-2861 ◽  
Author(s):  
Moua Yang ◽  
Andaleb Kholmukhamedov ◽  
Marie L. Schulte ◽  
Brian C. Cooley ◽  
Na’il O. Scoggins ◽  
...  
Keyword(s):  
Platelet Reactivity ◽  
Low Density Lipoprotein ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Signaling Molecules ◽  
Chow Diet ◽  
Glycoprotein Vi ◽  
Platelet Signaling ◽  
Clinically Significant

Abstract Dyslipidemia is a risk factor for clinically significant thrombotic events. In this condition, scavenger receptor CD36 potentiates platelet reactivity through recognition of circulating oxidized lipids. CD36 promotes thrombosis by activating redox-sensitive signaling molecules, such as the MAPK extracellular signal-regulated kinase 5 (ERK5). However, the events downstream of platelet ERK5 are not clear. In this study, we report that oxidized low-density lipoprotein (oxLDL) promotes exposure of procoagulant phosphatidylserine (PSer) on platelet surfaces. Studies using pharmacologic inhibitors indicate that oxLDL-CD36 interaction–induced PSer exposure requires apoptotic caspases in addition to the downstream CD36-signaling molecules Src kinases, hydrogen peroxide, and ERK5. Caspases promote PSer exposure and, subsequently, recruitment of the prothrombinase complex, resulting in the generation of fibrin from the activation of thrombin. Caspase activity was observed when platelets were stimulated with oxLDL. This was prevented by inhibiting CD36 and ERK5. Furthermore, oxLDL potentiates convulxin/glycoprotein VI–mediated fibrin formation by platelets, which was prevented when CD36, ERK5, and caspases were inhibited. Using 2 in vivo arterial thrombosis models in apoE-null hyperlipidemic mice demonstrated enhanced arterial fibrin accumulation upon vessel injury. Importantly, absence of ERK5 in platelets or mice lacking CD36 displayed decreased fibrin accumulation in high-fat diet–fed conditions comparable to that seen in chow diet–fed animals. These findings suggest that platelet signaling through CD36 and ERK5 induces a procoagulant phenotype in the hyperlipidemic environment by enhancing caspase-mediated PSer exposure.

The functions of Reelin in membrane trafficking and cytoskeletal dynamics: implications for neuronal migration, polarization and differentiation

2017 ◽  
Vol 474 (18) ◽  
pp. 3137-3165 ◽  
Author(s):  
Jessica Santana ◽  
María-Paz Marzolo
Keyword(s):  
Membrane Trafficking ◽  
Neuronal Migration ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Signaling Cascade ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Density Lipoprotein Receptor ◽  
Reelin Signaling

Reelin is a large extracellular matrix protein with relevant roles in mammalian central nervous system including neurogenesis, neuronal polarization and migration during development; and synaptic plasticity with its implications in learning and memory, in the adult. Dysfunctions in reelin signaling are associated with brain lamination defects such as lissencephaly, but also with neuropsychiatric diseases like autism, schizophrenia and depression as well with neurodegeneration. Reelin signaling involves a core pathway that activates upon reelin binding to its receptors, particularly ApoER2 (apolipoprotein E receptor 2)/LRP8 (low-density lipoprotein receptor-related protein 8) and very low-density lipoprotein receptor, followed by Src/Fyn-mediated phosphorylation of the adaptor protein Dab1 (Disabled-1). Phosphorylated Dab1 (pDab1) is a hub in the signaling cascade, from which several other downstream pathways diverge reflecting the different roles of reelin. Many of these pathways affect the dynamics of the actin and microtubular cytoskeleton, as well as membrane trafficking through the regulation of the activity of small GTPases, including the Rho and Rap families and molecules involved in cell polarity. The complexity of reelin functions is reflected by the fact that, even now, the precise mode of action of this signaling cascade in vivo at the cellular and molecular levels remains unclear. This review addresses and discusses in detail the participation of reelin in the processes underlying neurogenesis, neuronal migration in the cerebral cortex and the hippocampus; and the polarization, differentiation and maturation processes that neurons experiment in order to be functional in the adult brain. In vivo and in vitro evidence is presented in order to facilitate a better understanding of this fascinating system.

scholarly journals Receptor Clustering Is Involved in Reelin Signaling

2004 ◽  
Vol 24 (3) ◽  
pp. 1378-1386 ◽  
Author(s):  
Vera Strasser ◽  
Daniela Fasching ◽  
Christoph Hauser ◽  
Harald Mayer ◽  
Hans H. Bock ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Low Density Lipoprotein ◽  
Hippocampal Slices ◽  
Density Lipoprotein ◽  
Adaptor Protein ◽  
Long Term Potentiation ◽  
Hek293 Cells ◽  
Akt Phosphorylation ◽  
Reelin Signaling

ABSTRACT The Reelin signaling cascade plays a crucial role in the correct positioning of neurons during embryonic brain development. Reelin binding to apolipoprotein E receptor 2 (ApoER2) and very-low-density-lipoprotein receptor (VLDLR) leads to phosphorylation of disabled 1 (Dab1), an adaptor protein which associates with the intracellular domains of both receptors. Coreceptors for Reelin have been postulated to be necessary for Dab1 phosphorylation. We show that bivalent agents specifically binding to ApoER2 or VLDLR are sufficient to mimic the Reelin signal. These agents induce Dab1 phosphorylation, activate members of the Src family of nonreceptor tyrosine kinases, modulate protein kinase B/Akt phosphorylation, and increase long-term potentiation in hippocampal slices. Induced dimerization of Dab1 in HEK293 cells leads to its phosphorylation even in the absence of Reelin receptors. The mechanism for and the sites of these phosphorylations are identical to those effected by Reelin in primary neurons. These results suggest that binding of Reelin, which exists as a homodimer in vivo, to ApoER2 and VLDLR induces clustering of ApoER2 and VLDLR. As a consequence, Dab1 becomes dimerized or oligomerized on the cytosolic side of the plasma membrane, constituting the active substrate for the kinase; this process seems to be sufficient to transmit the signal and does not appear to require any coreceptor.

scholarly journals Scavenger Receptor CD36 Directs Nonclassical Monocyte Patrolling Along the Endothelium During Early Atherogenesis

2017 ◽  
Vol 37 (11) ◽  
pp. 2043-2052 ◽  
Author(s):  
Paola M. Marcovecchio ◽  
Graham D. Thomas ◽  
Zbigniew Mikulski ◽  
Erik Ehinger ◽  
Karin A.L. Mueller ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Adaptor Protein ◽  
Fold Increase ◽  
Vascular Wall ◽  
Western Diet ◽  
Oxidized Lipoprotein

Objective— Nonclassical monocytes (NCM) function to maintain vascular homeostasis by crawling or patrolling along the vessel wall. This subset of monocytes responds to viruses, tumor cells, and other pathogens to aid in protection of the host. In this study, we wished to determine how early atherogenesis impacts NCM patrolling in the vasculature. Approach and Results— To study the role of NCM in early atherogenesis, we quantified the patrolling behaviors of NCM in ApoE −/− (apolipoprotein E) and C57BL/6J mice fed a Western diet. Using intravital imaging, we found that NCM from Western diet–fed mice display a 4-fold increase in patrolling activity within large peripheral blood vessels. Both human and mouse NCM preferentially engulfed OxLDL (oxidized low-density lipoprotein) in the vasculature, and we observed that OxLDL selectively induced NCM patrolling in vivo. Induction of patrolling during early atherogenesis required scavenger receptor CD36, as CD36 −/− mice revealed a significant reduction in patrolling activity along the femoral vasculature. Mechanistically, we found that CD36-regulated patrolling was mediated by a SFK (src family kinase) through DAP12 (DNAX activating protein of 12KDa) adaptor protein. Conclusions— Our studies show a novel pathway for induction of NCM patrolling along the vascular wall during early atherogenesis. Mice fed a Western diet showed increased NCM patrolling activity with a concurrent increase in SFK phosphorylation. This patrolling activity was lost in the absence of either CD36 or DAP12. These data suggest that NCM function in an atheroprotective manner through sensing and responding to oxidized lipoprotein moieties via scavenger receptor engagement during early atherogenesis.

scholarly journals Platelet Activation by Oxidized Low Density Lipoprotein Is Mediated by Cd36 and Scavenger Receptor-A

2007 ◽  
Vol 27 (11) ◽  
pp. 2476-2483 ◽  
Author(s):  
Suzanne J.A. Korporaal ◽  
Miranda Van Eck ◽  
Jelle Adelmeijer ◽  
Martin Ijsseldijk ◽  
Ruud Out ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Low Density Lipoprotein ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein ◽  
Scavenger Receptor A

scholarly journals PCSK9 (Proprotein Convertase Subtilisin/Kexin 9) Enhances Platelet Activation, Thrombosis, and Myocardial Infarct Expansion by Binding to Platelet CD36

Circulation ◽  
2021 ◽  
Vol 143 (1) ◽  
pp. 45-61 ◽  
Author(s):  
Zhiyong Qi ◽  
Liang Hu ◽  
Jianjun Zhang ◽  
Wenlong Yang ◽  
Xin Liu ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Low Density Lipoprotein ◽  
Atp Release ◽  
Density Lipoprotein ◽  
Dense Granule ◽  
Clot Retraction ◽  
Pcsk9 Inhibitors ◽  
Infarct Expansion ◽  
Underlying Mechanisms

Background: PCSK9 (proprotein convertase subtilisin/kexin 9), mainly secreted by the liver and released into the blood, elevates plasma low-density lipoprotein cholesterol by degrading low-density lipoprotein receptor. Pleiotropic effects of PCSK9 beyond lipid metabolism have been shown. However, the direct effects of PCSK9 on platelet activation and thrombosis, and the underlying mechanisms, as well, still remain unclear. Methods: We detected the direct effects of PCSK9 on agonist-induced platelet aggregation, dense granule ATP release, integrin αIIbβ3 activation, α-granule release, spreading, and clot retraction. These studies were complemented by in vivo analysis of FeCl 3 -injured mouse mesenteric arteriole thrombosis. We also investigated the underlying mechanisms. Using the myocardial infarction (MI) model, we explored the effects of PCSK9 on microvascular obstruction and infarct expansion post-MI. Results: PCSK9 directly enhances agonist-induced platelet aggregation, dense granule ATP release, integrin αIIbβ3 activation, P-selectin release from α-granules, spreading, and clot retraction. In line, PCSK9 enhances in vivo thrombosis in a FeCl 3 -injured mesenteric arteriole thrombosis mouse model, whereas PCSK9 inhibitor evolocumab ameliorates its enhancing effects. Mechanism studies revealed that PCSK9 binds to platelet CD36 and thus activates Src kinase and MAPK (mitogen-activated protein kinase)–extracellular signal-regulated kinase 5 and c-Jun N-terminal kinase, increases the generation of reactive oxygen species, and activates the p38MAPK/cytosolic phospholipase A2/cyclooxygenase-1/thromboxane A 2 signaling pathways downstream of CD36 to enhance platelet activation, as well. Using CD36 knockout mice, we showed that the enhancing effects of PCSK9 on platelet activation are CD36 dependent. It is important to note that aspirin consistently abolishes the enhancing effects of PCSK9 on platelet activation and in vivo thrombosis. Last, we showed that PCSK9 activating platelet CD36 aggravates microvascular obstruction and promotes MI expansion post-MI. Conclusions: PCSK9 in plasma directly enhances platelet activation and in vivo thrombosis, and MI expansion post-MI, as well, by binding to platelet CD36 and thus activating the downstream signaling pathways. PCSK9 inhibitors or aspirin abolish the enhancing effects of PCSK9, supporting the use of aspirin in patients with high plasma PCSK9 levels in addition to PCSK9 inhibitors to prevent thrombotic complications.

scholarly journals Human protein S inhibits the uptake of AcLDL and expression of SR-A through Mer receptor tyrosine kinase in human macrophages

Blood ◽  
2009 ◽  
Vol 113 (1) ◽  
pp. 165-174 ◽  
Author(s):  
Dan Liao ◽  
Xinwen Wang ◽  
Min Li ◽  
Peter H. Lin ◽  
Qizhi Yao ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Low Density Lipoprotein ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Immunohistochemical Analysis ◽  
Protein S ◽  
Human Protein ◽  
Blood Monocytes

Abstract Human protein S is an anticoagulation protein. However, it is unknown whether protein S could regulate the expression and function of macrophage scavenger receptor A (SR-A) in macrophages. Human THP-1 monocytes and peripheral blood monocytes were differentiated into macrophages and then treated with physiological concentrations of human protein S. We found that protein S significantly reduced acetylated low-density lipoprotein (AcLDL) uptake and binding by macrophages and decreased the intracellular cholesteryl ester content. Protein S suppressed the expression of the SR-A at both mRNA and protein levels. Protein S reduced the SR-A promoter activity primarily through inhibition in the binding of transcription factors to the AP-1 promoter element in macrophages. Furthermore, human protein S could bind and induce phosphorylation of Mer receptor tyrosine kinase (Mer RTK). Soluble Mer protein or tyrosine kinase inhibitor herbimycin A effectively blocked the effects of protein S on AcLDL uptake. Immunohistochemical analysis revealed that the level of protein S was substantially increased in human atherosclerotic arteries. Thus, human protein S can inhibit the expression and activity of SR-A through Mer RTK in macrophages, suggesting that human protein S is a modulator for macrophage functions in uptaking of modified lipoproteins.

Abstract 646: Redox Control of Macropinocytosis; An Unexplored Target in Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Pushpankur Ghoshal ◽  
Bhupesh Singla ◽  
Douglas Feck ◽  
Nadiezhda Cantu-Medellin ◽  
Eric Kelley ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Actin Binding ◽  
Lipid Uptake ◽  
Signaling Mechanism ◽  
Membrane Ruffling

Aims: Early studies established the paradigm that oxidation of low density lipoprotein (LDL) is necessary for scavenger receptor-mediated LDL uptake and lipid accumulation in macrophages. In addition to this “classical” mode of lipid internalization, scavenger receptor-independent uptake of native, non-oxidized LDL (nLDL) via macropinocytosis has been demonstrated to contribute to lipid uptake by macrophages. Despite this previous information the precise signaling mechanisms regulating macropinocytosis of nLDL and the relative contribution of lipid macropinocytosis to atherosclerosis remain unknown. This study was designed to examine the role of phagocyte NADPH oxidase (a.k.a. Nox2) in macropinocytosis and to investigate macropinocytotic uptake of lipids in hypercholesterolemic ApoE -/- mice in vivo . Results: Phorbol myristate acetate (4β-PMA) activation of human and murine macrophages stimulated membrane ruffling, macropinosome formation, and subsequent uptake of nLDL by macropinocytosis. FACS data indicated that 4β-PMA stimulates lipid accumulation following nLDL treatment in macrophages lacking scavenger receptor CD36. Mechanistically, we found that pharmacological blockade of protein kinase C (PKC), inhibition of flavoenzymes by diphenyleneiodonium, and scavenging intracellular superoxide anion abolished phorbol ester-induced macropinocytosis. Transcriptional knockdown of Nox2 using siRNA inhibited 4β-PMA-induced macropinocytosis in THP-1 macrophages. Delving further into the mechanism, we found that Nox2 via redox inactivation of PTEN and activation of the PI3K/Akt pathway dephosphorylates the actin-binding protein cofilin, stimulates membrane ruffling, and induces macropinocytosis. Finally, peritoneal chimera experiments indicate that macropinocytotic uptake of lipids in hypercholesterolemic ApoE -/- mice was attenuated in Nox2 y/- macrophages compared to wild type controls. Innovation and Conclusion: These findings suggest a previously undescribed redox-sensitive signaling pathway leading to internalization of nLDL by macropinocytosis. The signaling mechanism described herein may identify new targets in atherosclerosis and other disease conditions involving macropinocytosis.

Oxidation of Plasma Low-Density Lipoprotein Accelerates Its Accumulation and Degradation in the Arterial Wall In Vivo

Circulation ◽  
1996 ◽  
Vol 94 (7) ◽  
pp. 1698-1704 ◽  
Author(s):  
Klaus Juul ◽  
Lars B. Nielsen ◽  
Klaus Munkholm ◽  
Steen Stender ◽  
Børge G. Nordestgaard
Keyword(s):  
Arterial Wall ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density

scholarly journals Interaction of 4-hydroxynonenal-modified low-density lipoproteins with the fibroblast apolipoprotein B/E receptor

1986 ◽  
Vol 234 (1) ◽  
pp. 245-248 ◽  
Author(s):  
W Jessup ◽  
G Jurgens ◽  
J Lang ◽  
H Esterbauer ◽  
R T Dean
Keyword(s):  
Apolipoprotein B ◽  
Negative Charge ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lipid Peroxidation Product ◽  
Modified Low Density Lipoproteins ◽  
Peroxidation Product

The incorporation of the lipid peroxidation product 4-hydroxynonenal into low-density lipoprotein (LDL) increases the negative charge of the particle, and decreases its affinity for the fibroblast LDL receptor. It is suggested that this modification may occur in vivo, and might promote atherogenesis.

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