scholarly journals Regulated expression of CD36 during monocyte-to-macrophage differentiation: potential role of CD36 in foam cell formation

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 2020-2028 ◽  
Author(s):  
HY Huh ◽  
SF Pearce ◽  
LM Yesner ◽  
JL Schindler ◽  
RL Silverstein
Keyword(s):  
Monoclonal Antibodies ◽  
Plasma Membrane ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Mrna Levels ◽  
Macrophage Differentiation ◽  
Differentiation Potential ◽  
Intracellular Pool

CD36 is an 88-kD integral membrane glycoprotein expressed on monocytes, platelets, and certain microvascular endothelium serving distinct cellular functions both as an adhesive receptor for thrombospondin, collagen, and Plasmodium falciparum-infected erythrocytes, and as a scavenger receptor for oxidized low-density lipoprotein and apoptotic neutrophils. In this study, we examined the expression of CD36 during in vitro differentiation of peripheral blood monocytes into culture- derived macrophages. Steady-state mRNA levels of CD36 showed a transient eightfold increase during monocyte-to-macrophage differentiation, peaking at the early macrophage stage (days 3 or 4 in culture), following a gradual decrease back to baseline levels by the mature macrophage stage (days 7 or 8 in culture). Immunoblotting with monoclonal antibodies to CD36 supported this transient, yet significant (8- to 10-fold) increase in total protein levels of CD36. The increased CD36 protein was observed at the plasma membrane, whereas an intracellular pool of CD36 was also detected from day 2 to day 6 in culture through indirect immunofluorescence. A concomitant twofold increase in the cells' ability to bind 125I-thrombospondin at the early macrophage stage (day 4) verified the functional competency of the plasma membrane localized CD36, and supported the presence of an intracellular pool of CD36. The in vitro differentiated macrophages as well as alveolar macrophages remained responsive to macrophage colony- stimulating factor (M-CSF), a known transcriptional regulator of monocyte CD36. The M-CSF-induced macrophages resulted in enhanced foam cell formation, which was inhibitable with monoclonal antibodies to CD36. Thus, the transient expression of CD36 during monocyte-to- macrophage differentiation, and the ability of M-CSF to maintain macrophage CD36 at elevated levels, may serve as a critical process in dictating the functional activity of CD36 during inflammatory responses and atherogenesis.

scholarly journals Regulated expression of CD36 during monocyte-to-macrophage differentiation: potential role of CD36 in foam cell formation

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 2020-2028 ◽  
Author(s):  
HY Huh ◽  
SF Pearce ◽  
LM Yesner ◽  
JL Schindler ◽  
RL Silverstein
Keyword(s):  
Monoclonal Antibodies ◽  
Plasma Membrane ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Mrna Levels ◽  
Macrophage Differentiation ◽  
Differentiation Potential ◽  
Intracellular Pool

Abstract CD36 is an 88-kD integral membrane glycoprotein expressed on monocytes, platelets, and certain microvascular endothelium serving distinct cellular functions both as an adhesive receptor for thrombospondin, collagen, and Plasmodium falciparum-infected erythrocytes, and as a scavenger receptor for oxidized low-density lipoprotein and apoptotic neutrophils. In this study, we examined the expression of CD36 during in vitro differentiation of peripheral blood monocytes into culture- derived macrophages. Steady-state mRNA levels of CD36 showed a transient eightfold increase during monocyte-to-macrophage differentiation, peaking at the early macrophage stage (days 3 or 4 in culture), following a gradual decrease back to baseline levels by the mature macrophage stage (days 7 or 8 in culture). Immunoblotting with monoclonal antibodies to CD36 supported this transient, yet significant (8- to 10-fold) increase in total protein levels of CD36. The increased CD36 protein was observed at the plasma membrane, whereas an intracellular pool of CD36 was also detected from day 2 to day 6 in culture through indirect immunofluorescence. A concomitant twofold increase in the cells' ability to bind 125I-thrombospondin at the early macrophage stage (day 4) verified the functional competency of the plasma membrane localized CD36, and supported the presence of an intracellular pool of CD36. The in vitro differentiated macrophages as well as alveolar macrophages remained responsive to macrophage colony- stimulating factor (M-CSF), a known transcriptional regulator of monocyte CD36. The M-CSF-induced macrophages resulted in enhanced foam cell formation, which was inhibitable with monoclonal antibodies to CD36. Thus, the transient expression of CD36 during monocyte-to- macrophage differentiation, and the ability of M-CSF to maintain macrophage CD36 at elevated levels, may serve as a critical process in dictating the functional activity of CD36 during inflammatory responses and atherogenesis.

Abstract 18340: Alternatively Spliced Tissue Factor Promotes Atherosclerosis by Increasing Foam Cell Formation via LOX-1 and SR-A1 up-regulation

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Daniel Alicea ◽  
Saboor Hekmaty ◽  
David T Rodriguez ◽  
Peter Bhandari ◽  
Dong Kwong Yang ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Lipid Accumulation ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cells ◽  
Scavenger Receptors ◽  
Foam Cell Formation ◽  
Mrna Levels ◽  
Plaque Progression

Introduction: Alternatively Spliced Tissue Factor (asTF) is an isoform of tissue factor that is expressed in human atherosclerotic plaques and promotes plaque progression in experimental atherosclerosis (Giannarelli C, Circulation 2014). Hypothesis: asTF is the isoform of tissue factor that most strongly promotes atherosclerosis by increasing foam cell formation. Methods: ApoE-/- mice (8 weeks old) were fed a Western-type diet starting 2 weeks before surgery. Immediately after transluminal wire injury of the left common carotid artery (LCCA), LCCA was incubated with lentivirus encoding asTF-GFP (asTF+;n=10), fl-TF-GFP (fl-TF+, n=10) or GFP (controls; n=5). Four weeks after, LCCA was removed and processed for the quantification of plaque size (H&E) and lipid accumulation (Oil-Red O). The effect of asTF on foam cell formation was tested in vitro by treating THP-1 derived macrophages with oxLDL (75μg/ml), with asTF (10nM) or vehicle. Total cholesterol (TC) and cholesterol esters (CE) were measured in lipid cell extracts. The mRNA levels of the oxLDL scavenger receptors LOX-1, SR-A1 and CD36 in macrophages and foam cells were assessed using qRT-PCR. Results: Plaque size and lipid accumulation were significantly greater in asTF+ vs. fl-TF+ and control mice (Fig.1, A-D). In vitro results showed that asTF promotes TC and CE accumulation in foam cells (Fig.1, E,F). Gene expression studies showed that asTF significantly increased the mRNA expression of scavenger receptors LOX-1, SR-A1 in both macrophages and foam cells (Fig.1, G-I). An increase in mRNA levels of CD36 (1.4-fold) was only detected in asTF-treated foam cells. Conclusions: In vivo results suggest that asTF promote plaque progression and lipid accumulation. In vitro studies imply that asTF promotes foam cell formation by increasing the expression of oxLDL scavenger receptors implicated in lipoprotein uptake by macrophages. These studies suggest a functional role for asTF in atherosclerotic plaque progression.

Abstract 3691: Deletion of Suppressor Of Cytokine Signaling-1 in a Murine Model of Atherosclerosis Results in a Lethal Systemic Inflammation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Christina Grothusen ◽  
Harald Schuett ◽  
Stefan Lumpe ◽  
Andre Bleich ◽  
Silke Glage ◽  
...  
Keyword(s):  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
The Impact

Introduction: Atherosclerosis is a chronic inflammatory disease of the cardiovascular system which may result in myocardial infarction and sudden cardiac death. While the role of pro-inflammatory signaling pathways in atherogenesis has been well characterized, the impact of their negative regulators, e.g. suppressor of cytokine signaling (SOCS)-1 remains to be elucidated. Deficiency of SOCS-1 leads to death 3 weeks post-partum due to an overwhelming inflammation caused by an uncontrolled signalling of interferon-gamma (IFNγ). This phenotype can be rescued by generating recombination activating gene (rag)-2, SOCS-1 double knock out (KO) mice lacking mature lymphocytes, the major source of IFNγ. Since the role of SOCS-1 during atherogenesis is unknown, we investigated the impact of a systemic SOCS-1 deficiency in the low-density lipoprotein receptor (ldlr) KO model of atherosclerosis. Material and Methods: socs-1 −/− /rag-2 −/− deficient mice were crossed with ldlr-KO animals. Mice were kept under sterile conditions on a normal chow diet. For in-vitro analyses, murine socs-1 −/− macrophages were stimulated with native low density lipoprotein (nLDL) or oxidized (ox)LDL. SOCS-1 expression was determined by quantitative PCR and western blot. Foam cell formation was determined by Oil red O staining. Results: socs-1 −/− /rag-2 −/− /ldlr −/− mice were born according to mendelian law. Tripel-KO mice showed a reduced weight and size, were more sensitive to bacterial infections and died within 120 days (N=17). Histological analyses revealed a systemic, necrotic, inflammation in Tripel-KO mice. All other genotypes developed no phenotype. In-vitro observations revealed that SOCS-1 mRNA and protein is upregulated in response to stimulation with oxLDL but not with nLDL. Foam cell formation of socs-1 −/− macrophages was increased compared to controls. Conclusion: SOCS-1 seemingly controls critical steps of atherogenesis by modulating foam cell formation in response to stimulation with oxLDL. SOCS-1 deficiency in the ldlr-KO mouse leads to a lethal inflammation. These observations suggest a critical role for SOCS-1 in the regulation of early inflammatory responses in atherogenesis.

Abstract 276: Shockwave Reduces Macrophage Foam Cell Formation Via Increased Expression of ATP Binding Cassette Transporters.

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Wonkyoung Cho ◽  
Young Eun Yoon ◽  
Kihwan Kwon ◽  
Young Mi Park
Keyword(s):  
Western Blot ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Atp Binding ◽  
Mrna Levels ◽  
Macrophage Foam Cell ◽  
Migration Assay ◽  
Intracellular Cholesterol ◽  
Atp Binding Cassette

Background: Excessive lipid accumulation by macrophages plays a crucial role in atherosclerosis. Foam cells are generated by uncontrolled uptake of modified LDL, especially oxidized LDL (oxLDL), and/or impaired cholesterol efflux mediated by ATP-binding cassette (ABC) family transporters, ABCA-1 and ABCG-1. Shockwave, elicited by transient pressure disturbance, have been used for extracorporeal lithotripsy or for treating musculoskeletal disorders. Our current study suggests an evidence that shockwave may have anti-atherogenic effect by inhibiting foam cell formation. Methods/Results: Murine peritoneal macrophages were exposed to shockwaves at 0.04 mJ/mm 2 with 1000 impulses, lysed after 6, 18 and 24 hours, and tested for expression of ABCA-1 and ABCG-1. The western blot showed that shockwave induced 2.0-2.8 fold increase of ABCA-1 and ABCG-1 within 18-24 hours. mRNA levels of ABCA-1 and ABCG-1 were also increased by shockwave with 2.0 fold of peak increase in 18 hours. The increased expression of ABCA-1 and ABCG-1 was mediated by phosphorylation of ERK 1/2 (Tyr204). Western blot analysis revealed that shockwave induced phosphorylation of ERK 1/2 (Tyr204) in murine macrophages. Shockwave-induced increase of ABCA-1 and ABCG-1 was blocked by U0126 (40µM), a specific inhibitor for ERK. Oil-red O staining showed that macrophages exposed to shockwave had 25% less intracellular lipid droplets. Intracellular cholesterol measured by cholesterol oxidase and esterase revealed that macrophages exposed to shockwave had 23% less intracellular cholesterol when incubated with oxLDL (50µg/ml) for 16 hours. In vitro migration assays including modified Boyden chamber migration assay and scratch wound healing migration assay showed that macrophages exposed to shockwave had 1.2 fold more migration and had diminished migration-inhibitory effect of oxLDL. Conclusions: Shockwave reduces macrophage foam cell formation via ERK-mediated increase of ABCA-1 and ABCG-1 mediating lipid efflux and promotes macrophage migration which may induce macrophage egress from atherosclerotic lesion. Our study suggests anti-atherogenic effects of shockwave as a potential treatment modality for atherosclerosis.

Abstract 450: Modification of HDL by Reactive Aldehydes Impairs HDL's Athero-protective Functions

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Rebecca L Holme ◽  
Alexandra C Chadwick ◽  
Sarah C Proudfoot ◽  
Yiliang Chen ◽  
Devi Prasadh Ramakrishnan ◽  
...  
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Oxidative Modification ◽  
High Density Lipoproteins ◽  
Foam Cell Formation ◽  
Macrophage Migration ◽  
Mrna Levels ◽  
Protective Effects ◽  
Impaired Ability ◽  
Reactive Aldehydes

High density lipoproteins (HDL) are athero-protective particles that promote the removal of excess cholesterol from lipid-loaded macrophages and stimulate their migration in order to protect against foam cell formation, a precursor to atherosclerotic plaque build-up. Recently, studies have shown that oxidative modification of HDL prevents HDL from protecting against atherosclerosis; however, the exact mechanisms by which this occurs are not well defined. We hypothesize that oxidative modification of HDL by reactive aldehydes such as acrolein (a major component of cigarette smoke) and 4-hydroxynonenal (HNE; a product of lipid peroxidation) impairs HDL’s athero-protective effects in macrophages. We tested our hypothesis using three different assays. First, we determined that modified forms of HDL upregulate mRNA levels of pro-atherogenic scavenger receptors such as cluster of differentiation 36 (CD36), a known oxidized LDL receptor. Incubation of macrophages with native HDL did not exert similar effects. Second, we tested the ability of oxidized HDL to prevent foam cell formation. Peritoneal macrophages isolated from WT C57Bl/J mice were cholesterol-loaded and incubated with native HDL, acrolein-modified HDL (acro-HDL), or HNE-modified HDL (HNE-HDL). Oil Red-O staining demonstrated that 24% of macrophages had foam cell formation upon incubation with native HDL, whereas 61% and 49% foam cell formation was observed for acro- and HNE-HDL, respectively. Preliminary data suggests this may be CD36-dependent. Finally, using a Boyden chamber assay, we demonstrated that both acro- and HNE-HDL, but not native HDL, had an impaired ability to promote macrophage migration (43% and 72% of HDL cell migration levels, respectively). We determined that the inability of acro- and/or HNE-HDL to stimulate macrophage migration may be due to an impaired ability of these modified lipoproteins to activate the PI3K pathway, as shown by decreased levels of phosphorylated protein kinase B (Akt). In conclusion, we have identified three independent mechanisms by which modification of HDL with acrolein or HNE impairs HDL’s cardio-protective effects and, instead, generates a particle that promotes pathways that lead to atherosclerosis.

Abstract 424: An IFNg-regulated Macrophage Protein Network Links Type 2 Diabetes to Atherosclerosis

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Catherine A Reardon ◽  
Amulya Lingaraju ◽  
Kelly Q Schoenfelt ◽  
Guolin Zhou ◽  
Ning-Chun Liu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Increased Risk ◽  
Macrophage Dysfunction ◽  
Macrophage Protein

Type 2 diabetics have a higher risk for atherosclerosis, but the mechanisms underlying the increased risk are poorly understood. Macrophages, which are activated in type 2 diabetes (T2D) and have a role in all stages of atherogenesis, are an attractive link. Our hypothesis is that T2D promotes macrophage dysfunction to promote atherosclerosis. To investigate the relationship between T2D and macrophage dysfunction, we used a proteomics approach to identify dysregulated proteins secreted from peritoneal macrophages in a diet induced mouse model of obesity and insulin resistance in the absence of hypercholesterolemia. Twenty-seven T2D responsive proteins were identified that predict defects in many of the critical functions of macrophages in atherosclerosis (e.g. decreased apoE- cholesterol efflux; decreased MFGE8 – efferocytosis, increased MMP12- matrix degradation). The macrophages from lean and obese mice were not lipid loaded, but the obese macrophages accumulated significantly more cholesterol when exposed to high levels of atherogenic lipoproteins in vitro suggesting that dysregulation of the T2D responsive proteins in diabetic mice render macrophages more susceptible to cholesterol loading. Importantly, many of these same protein changes, which were present in atherosclerotic Ldlr-/- mice with T2D, were normalized when these mice were fed non-diabetogenic hypercholesterolemic diets. Thus, foam cell formation in the presence and absence of T2D produces distinct effects on macrophage protein levels, and hence function. Further, we identify IFNγ as a mediator of the T2D responsive protein dysfunction. IFNγ, but not other cytokines, insulin or glucose, promote the T2D responsive protein dysregulation and increased susceptibility to cholesterol accumulation in vitro and the dysregulation is not observed in macrophage foam cells obtained from obese, diabetic IFNγ receptor 1 knockout animals. We also demonstrate that IFNγ can target these proteins in arterial wall macrophages in vivo . These studies suggest that IFNγ is an important mediator of macrophage dysfunction in T2D that may contribute to the enhanced cardiovascular risk in these patients.

P209 GLYCATED LDL STIMULATE FOAM CELL FORMATION IN VITRO AND LDL GLYCATION IS OPPOSED BY PARAOXONASE-RICH HDL

2010 ◽  
Vol 11 (2) ◽  
pp. 60
Author(s):  
N. Younis ◽  
H. Soran ◽  
R. Sharma ◽  
P. Pemberton ◽  
V. Charlton-Menys ◽  
...  
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Glycated Ldl

Influence of minor components of olive oils on the composition and size of TRLs and on macrophage receptors involved in foam cell formation

2007 ◽  
Vol 35 (3) ◽  
pp. 470-471 ◽  
Author(s):  
R. Cabello-Moruno ◽  
J.S. Perona ◽  
V. Ruiz-Gutierrez
Keyword(s):  
Dietary Fat ◽  
Foam Cell ◽  
Cell Formation ◽  
Epidemiologic Studies ◽  
Dietary Fats ◽  
Foam Cell Formation ◽  
Minor Components ◽  
Cardiovascular Heart Disease ◽  
Macrophage Receptors

Metabolic and epidemiologic studies support the idea that the type of dietary fat is more important than the total amount of fat with respect to the development of atherosclerosis and the risk of cardiovascular heart disease. Dietary fat is carried in CMs (chylomicrons), which can be taken up by macrophages without need of further oxidation, leading to the formation of foam cells and initiating or aggravating the atherogenic process. Evidence from different studies has shown that dietary fat can influence the composition and size of TRLs (triacylglycerol-rich lipoproteins), which might modulate their atherogenicity to a certain extent. In particular, experiments in vitro have shown the anti-atherogenic effects of minor components from olive oil when forming part of TRL, as these particles give minor lipid components the opportunity to interact with the cells implicated in endothelial dysfunction and atherogenesis. However, the exact mechanisms mediating CM uptake by macrophages still remain unclear. Thus further studies are needed to understand how the modifications of TRL composition caused by dietary fats could modulate the expression of macrophage receptors and foam cell formation, or even improve the atherogenic risk of these particles.

scholarly journals Dysfunctional high-density lipoprotein from HIV+ individuals promotes monocyte-derived foam cell formation in vitro

AIDS ◽  
2017 ◽  
Vol 31 (17) ◽  
pp. 2331-2336 ◽  
Author(s):  
Thomas A. Angelovich ◽  
Anna C. Hearps ◽  
Michael N. Oda ◽  
Mark S. Borja ◽  
Diana Huynh ◽  
...  
Keyword(s):  
High Density Lipoprotein ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
High Density ◽  
Foam Cell Formation
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