Pu-erh Tea Extract Attenuates Nicotine-Induced Foam Cell Formation in Primary Cultured Monocytes: An in Vitro Mechanistic Study

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.

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Regulation of lipoprotein lipase secretion in murine macrophages during foam cell formation in vitro. Effect of triglyceride-rich lipoproteins.

Arteriosclerosis and Thrombosis A Journal of Vascular Biology ◽

10.1161/01.atv.12.12.1458 ◽

1992 ◽

Vol 12 (12) ◽

pp. 1458-1466 ◽

Cited By ~ 11

Author(s):

O Sofer ◽

M Fainaru ◽

Z Schafer ◽

R Goldman

Keyword(s):

Lipoprotein Lipase ◽

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

Murine Macrophages ◽

Vitro Effect

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

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.424 ◽

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.

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

Atherosclerosis Supplements ◽

10.1016/s1567-5688(10)70276-2 ◽

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

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

Blood ◽

10.1182/blood.v87.5.2020.2020 ◽

1996 ◽

Vol 87 (5) ◽

pp. 2020-2028 ◽

Cited By ~ 192

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.

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Mindin deficiency in macrophages protects against foam cell formation and atherosclerosis by targeting LXR-β

Clinical Science ◽

10.1042/cs20180033 ◽

2018 ◽

Vol 132 (11) ◽

pp. 1199-1213 ◽

Cited By ~ 4

Author(s):

Cheng Zhang ◽

Juan-Juan Qin ◽

Fu-Han Gong ◽

Jing-Jing Tong ◽

Wen-Lin Cheng ◽

...

Keyword(s):

High Fat Diet ◽

Matrix Protein ◽

Foam Cell ◽

Cell Formation ◽

Direct Interaction ◽

Extracellular Matrix Protein ◽

Mechanistic Study ◽

Foam Cell Formation ◽

Atheromatous Plaques ◽

Inflammatory Processes

Mindin, which is a highly conserved extracellular matrix protein, has been documented to play pivotal roles in regulating angiogenesis, inflammatory processes, and immune responses. The aim of the present study was to assess whether mindin contributes to the development of atherosclerosis. A significant up-regulation of Mindin expression was observed in the serum, arteries and atheromatous plaques of ApoE−/− mice after high-fat diet treatment. Mindin−/−ApoE−/− mice and macrophage-specific mindin overexpression in ApoE−/− mice (Lyz2-mindin-TG) were generated to evaluate the effect of mindin on the development of atherosclerosis. The Mindin−/−ApoE−/− mice exhibited significantly ameliorated atherosclerotic burdens in the entire aorta and aortic root and increased atherosclerotic plaque stability. Moreover, bone marrow transplantation further demonstrated that mindin deficiency in macrophages was largely responsible for the alleviated atherogenesis. The Lyz2-mindin-TG mice exhibited the opposite phenotype. Mindin deficiency enhanced foam cell formation by increasing the expression of cholesterol effectors, including ABCA1 and ABCG1. The mechanistic study indicated that mindin ablation promoted LXR-β expression via a direct interaction. Importantly, LXR-β inhibition largely reversed the ameliorating effect of mindin deficiency on foam cell formation and ABCA1 and ABCG1 expression. The present study demonstrated that mindin deficiency serves as a novel mediator that protects against foam cell formation and atherosclerosis by directly interacting with LXR-β.

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

Biochemical Society Transactions ◽

10.1042/bst0350470 ◽

2007 ◽

Vol 35 (3) ◽

pp. 470-471 ◽

Cited By ~ 10

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.

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

AIDS ◽

10.1097/qad.0000000000001642 ◽

2017 ◽

Vol 31 (17) ◽

pp. 2331-2336 ◽

Cited By ~ 8

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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Modeling early stage atherosclerosis in a primary human vascular microphysiological system

Nature Communications ◽

10.1038/s41467-020-19197-8 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Xu Zhang ◽

Muath Bishawi ◽

Ge Zhang ◽

Varun Prasad ◽

Ellen Salmon ◽

...

Keyword(s):

Cell Activation ◽

Foam Cell ◽

Early Stage ◽

Cell Formation ◽

Density Lipoprotein ◽

Foam Cell Formation ◽

No Production ◽

Endothelial Cell Activation

Abstract Novel atherosclerosis models are needed to guide clinical therapy. Here, we report an in vitro model of early atherosclerosis by fabricating and perfusing multi-layer arteriole-scale human tissue-engineered blood vessels (TEBVs) by plastic compression. TEBVs maintain mechanical strength, vasoactivity, and nitric oxide (NO) production for at least 4 weeks. Perfusion of TEBVs at a physiological shear stress with enzyme-modified low-density-lipoprotein (eLDL) with or without TNFα promotes monocyte accumulation, reduces vasoactivity, alters NO production, which leads to endothelial cell activation, monocyte accumulation, foam cell formation and expression of pro-inflammatory cytokines. Removing eLDL leads to recovery of vasoactivity, but not loss of foam cells or recovery of permeability, while pretreatment with lovastatin or the P2Y11 inhibitor NF157 reduces monocyte accumulation and blocks foam cell formation. Perfusion with blood leads to increased monocyte adhesion. This atherosclerosis model can identify the role of drugs on specific vascular functions that cannot be assessed in vivo.

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