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 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.

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.

Quantitative analysis of blood vessel permeability of squirrel monkeys

1991 ◽  
Vol 260 (4) ◽  
pp. H1194-H1204 ◽  
Author(s):  
R. G. Tompkins
Keyword(s):  
Transport Model ◽  
Low Density Lipoprotein ◽  
Effective Diffusion ◽  
Density Lipoprotein ◽  
Vascular Wall ◽  
Squirrel Monkeys ◽  
Regression Methods ◽  
Ldl Transport ◽  
Ldl Uptake

A mathematical transport model was derived to analyze in vivo low-density lipoprotein (LDL) transport across the aorta, peripheral muscular arteries, and major veins of squirrel monkeys (primates that develop diet-induced atherosclerosis similar to humans). Parameters determining the relative magnitudes of intimal permeability and diffusion within the vascular wall were optimized by nonlinear regression methods. Transmural LDL concentrations demonstrating discrete spatial resolution along the endothelial surface were previously obtained after 30 min of tracer circulation using quantitative autoradiography. In this study, intimal mass transfer coefficient (k1) was determined in 87 vascular regions representing 280 transmural profiles. As a result of this analysis, the value of k1 was 1.7 +/- 0.4 x 10(-9) cm/s for arteries, 2.9 +/- 0.3 x 10(-9) cm/s for veins, and 60 +/- 120 x 10(-9) cm/s for enhanced LDL uptake regions, which was a significant increase (P less than 0.01). The effective diffusion coefficient was 6.2 +/- 3.7 x 10(-10) cm2/s for all vascular regions examined. As a result of this analysis, focal regions of enhanced LDL uptake were explained solely on the basis of intimal permeability.

scholarly journals Polar phospholipids from bovine endogenously oxidized low density lipoprotein interfere with follicular thecal function

2005 ◽  
Vol 35 (3) ◽  
pp. 531-545 ◽  
Author(s):  
B Löhrke ◽  
T Viergutz ◽  
B Krüger
Keyword(s):  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Ldl Oxidation ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein ◽  
Steroidogenic Enzymes ◽  
Cox 2

The role of endogenously oxidized low density lipoprotein (oxLDL) in follicular steroidogenic regulation is unknown. Information may be important in order to elucidate ovulatory dysregulation in disordered lipid metabolism. To obtain specific data, we studied the effect of polar phospholipids (PL) isolated from oxLDL with different endogenous levels of lipohydroperoxides (LHP) on the thecal expression of mRNA encoding steroidogenic enzymes and cyclooxygenase 2 (COX-2), and on the thecal production of superoxide and progesterone. Large (preovulatory) bovine follicles were used and analyses of thecal fragments from single follicles were performed by radioimmunoassays, chemiluminescence assays and quantitative RT-PCR. Basal concentration of mRNA for several lipoprotein receptors exceeded by about 10-times the basal level of mRNA encoding steroidogenic enzymes, suggesting that preovulatory theca receptors may favour uptake of oxLDL. PL (5–11 pmol phosphorus/ml) decreased (up to 0.5-times the control) progesterone synthesis, production of superoxide and levels of P450 cholesterol side chain cleavage (P450 scc), 3β-hydroxysteroid dehydrogenase and COX-2 mRNA. Abundance of COX-2 transcripts in thecal tissue incubated with forskolin depended on the progesterone/17β-oestradiol ratio of the follicle fluid, i.e. the previous microenvironment in vivo. PL effects were mimicked by the platelet-activating factor (PAF). WEB 2086, a PAF receptor blocker, did not always abolish these responses, suggesting that the effects were not mediated solely by this receptor. PAF interfered dose-dependently with LH-induced responses, indicating interference with LH signalling. PL from mildly oxidized LDL (0.5 nmol/ml LHP) tended to exert greater effects than PL from oxLDL containing 1.5 nmol/ml LHP. In consideration of the known physiologic role of progesterone, COX-2 and possibly superoxide, these results provide evidence for a potential of PL from oxLDL to induce ovulatory dysregulation and suggest that the extent of the LDL oxidation seems to be important for interfering with thecal responses to the preovulatory LH surge.

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 Wide Biological Role of Hydroxytyrosol: Possible Therapeutic and Preventive Properties in Cardiovascular Diseases

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1932
Author(s):  
Chiara D’Angelo ◽  
Sara Franceschelli ◽  
José Luis Quiles ◽  
Lorenza Speranza
Keyword(s):  
Cardiovascular Health ◽  
Biological Effects ◽  
Low Density Lipoprotein ◽  
Antioxidant Properties ◽  
Density Lipoprotein ◽  
In Vivo Models ◽  
And Oxidative Stress

The growing incidence of cardiovascular disease (CVD) has promoted investigations of natural molecules that could prevent and treat CVD. Among these, hydroxytyrosol, a polyphenolic compound of olive oil, is well known for its antioxidant, anti-inflammatory, and anti-atherogenic effects. Its strong antioxidant properties are due to the scavenging of radicals and the stimulation of synthesis and activity of antioxidant enzymes (SOD, CAT, HO-1, NOS, COX-2, GSH), which also limit the lipid peroxidation of low-density lipoprotein (LDL) cholesterol, a hallmark of atherosclerosis. Lowered inflammation and oxidative stress and an improved lipid profile were also demonstrated in healthy subjects as well as in metabolic syndrome patients after hydroxytyrosol (HT) supplementation. These results might open a new therapeutic scenario through personalized supplementation of HT in CVDs. This review is the first attempt to collect together scientific literature on HT in both in vitro and in vivo models, as well as in human clinical studies, describing its potential biological effects for cardiovascular health.

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