Vitamin E Supplementation of Human Macrophages Prevents Neither Foam Cell Formation Nor Increased Susceptibility of Foam Cells to Lysis by Oxidized LDL

Atherosclerosis is a major cause of human cardiovascular disease, which is the leading cause of mortality around the world. Various physiological and pathological processes are involved, including chronic inflammation, dysregulation of lipid metabolism, development of an environment characterized by oxidative stress and improper immune responses. Accordingly, the expansion of novel targets for the treatment of atherosclerosis is necessary. In this study, we focus on the role of foam cells in the development of atherosclerosis. The specific therapeutic goals associated with each stage in the formation of foam cells and the development of atherosclerosis will be considered. Processing and metabolism of cholesterol in the macrophage is one of the main steps in foam cell formation. Cholesterol processing involves lipid uptake, cholesterol esterification and cholesterol efflux, which ultimately leads to cholesterol equilibrium in the macrophage. Recently, many preclinical studies have appeared concerning the role of non-encoding RNAs in the formation of atherosclerotic lesions. Non-encoding RNAs, especially microRNAs, are considered regulators of lipid metabolism by affecting the expression of genes involved in the uptake (e.g., CD36 and LOX1) esterification (ACAT1) and efflux (ABCA1, ABCG1) of cholesterol. They are also able to regulate inflammatory pathways, produce cytokines and mediate foam cell apoptosis. We have reviewed important preclinical evidence of their therapeutic targeting in atherosclerosis, with a special focus on foam cell formation.

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Abstract: P1165 AGED GARLIC EXTRACT INHIBITS CD36 EXPRESSION AND FOAM CELL FORMATION IN HUMAN MACROPHAGES

Atherosclerosis Supplements ◽

10.1016/s1567-5688(09)71158-4 ◽

2009 ◽

Vol 10 (2) ◽

pp. e1191

Author(s):

N Morihara ◽

N Ide ◽

N Weiss

Keyword(s):

Foam Cell ◽

Cell Formation ◽

Garlic Extract ◽

Foam Cell Formation ◽

Aged Garlic Extract ◽

Human Macrophages ◽

Cd36 Expression ◽

Aged Garlic

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Decabromodiphenyl ether (BDE-209) enhances foam cell formation in human macrophages via augmenting Toll-like receptor 4-dependent lipid uptake

Food and Chemical Toxicology ◽

10.1016/j.fct.2018.09.024 ◽

2018 ◽

Vol 121 ◽

pp. 367-373 ◽

Cited By ~ 6

Author(s):

Hui Zhi ◽

Jiang-Ping Wu ◽

Lin-Ming Lu ◽

Yan Li ◽

Xiao-Yun Chen ◽

...

Keyword(s):

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

Lipid Uptake ◽

Toll Like Receptor ◽

Decabromodiphenyl Ether ◽

Toll Like Receptor 4 ◽

Human Macrophages ◽

Bde 209

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Abstract 3758: Preventive Effects of Heregulin-Beta1 on Macrophage Foam Cell Formation and Atherosclerosis

Circulation ◽

10.1161/circ.118.suppl_18.s_481-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Takuya Watanabe ◽

Yoshitaka Iso ◽

Shinji Koba ◽

Tetsuo Sakai ◽

Gang Xu ◽

...

Keyword(s):

Foam Cell ◽

Cell Formation ◽

Apolipoprotein A1 ◽

Foam Cell Formation ◽

Type I ◽

Macrophage Foam Cell ◽

Human Macrophages ◽

Coronary Syndrome ◽

Atherosclerotic Lesions ◽

Mild Hypertensive

Human heregulins, neuregulin-1 type I polypeptides known to activate proliferation, differentiation, and survival of glial cells, neurons, and myocytes, were recently found to be expressed in macrophage foam cells within human coronary atherosclerotic lesions. Macrophage foam cell formation, characterized by cholesterol ester (CE) accumulation, is modulated by scavenger receptor class A (SR-A), acyl-CoA:cholesterol acyltransferase-1 (ACAT1), and ATP-binding cassette transporter A1 (ABCA1). The present study clarified the functional roles of heregulins in macrophage foam cell formation and atherosclerosis. Plasma heregulin-beta1 levels were significantly decreased in 31 patients with acute coronary syndrome (ACS) and 33 patients with stable angina pectoris as compared with 34 mild hypertensive patients and 40 healthy volunteers (1.3+/−0.3, 2.0+/−0.4 versus 7.6+/−1.4, 8.2+/−1.2 ng/mL; at least P < 0.01). Immunoreactive heregulins and these receptor c-erbB3 were detectable within human coronary atherothrombosis obtained from ACS patients. In primary cultured human monocyte-macrophages, the expression of endogenous heregulins, heregulin-beta1, and c-erbB3 increased during monocytic differentiation into macrophages. In human macrophages differentiated by 7-day culture, exogenous heregulin-beta1, but not heregulin-alpha, significantly reduced acetylated low-density lipoprotein (acLDL)-induced CE accumulation by reducing SR-A and ACAT1 expression and by increasing ABCA1 expression at both mRNA and protein levels. Heregulin-beta1 significantly decreased endocytic uptake of [ 125 I]acLDL and increased cholesterol efflux by apolipoprotein A1 from human macrophages. Chronic infusion of heregulin-beta1 by osmotic mini-pumps into apolipoprotein E-deficient mice significantly suppressed the progression of macrophage-driven atherosclerotic lesions by 64%. Our study provides the first evidence that heregulin-beta1 may participate in anti-atherogenesis by suppressing macrophage foam cell formation via SR-A and ACAT1 down-regulation and ABCA1 up-regulation.

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Abstract 57: The Epigenetic Enzyme Kdm6b Controls the Pro-Fibrotic Transcriptome Signature of Foam Cells

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.57 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Annette E Neele ◽

Koen H Prange ◽

Marten A Hoeksema ◽

Saskia van der Velden ◽

Tina Lucas ◽

...

Keyword(s):

Foam Cell ◽

Smooth Muscle Actin ◽

Cell Formation ◽

Atherosclerotic Lesion ◽

Foam Cells ◽

Foam Cell Formation ◽

Cell Phenotype ◽

Sequencing Analysis ◽

Dependent Manner ◽

Alpha Smooth Muscle Actin

Aim: Foam cells are a key hallmark of atherosclerotic lesion formation. Within the atherosclerotic lesion macrophages scavenge modified lipoproteins and thereby acquire their foam cell characteristics. Besides their foam cell phenotype, macrophages can have specific inflammation regulatory functions in atherosclerotic lesions. Epigenetic pathways are crucial for monocyte to macrophage differentiation and activation. The H3K27 demethylase Kdm6b (also known as Jmjd3) is regulated in response to various triggers and regulates several modes of macrophage activation. Given the crucial role of macrophage foam cells in atherosclerosis, we here studied Kdm6b in peritoneal foam cells in order to identify regulated pathways. Material and Methods: A myeloid deficient Kdm6b mice (LysMCre-Kdm6b fl/fl ) was generated and bone marrow of Kdm6b wt or Kdm6b del mice was transplanted to irradiated Ldlr -/- mice which were fed a high fat diet for 9 weeks to induce foam cell formation. Peritoneal foam cells from Kdm6b del or Kdm6b wt mice were isolated and used for RNA-sequencing analysis. Results: Among the list of downregulated genes many genes involving fibrosis were affected in Kdm6b deficient foam cells including Collagen genes ( Col1a1 , Col1a2 ), Alpha smooth muscle actin ( Acta2 ) and Fibronectin-1 ( Fn1 ). Pathway analysis on downregulated genes ( P -value < 0.05) indicated that pathways involved in epithelial to mesenchymaltransition (EMT) ( q- value=10 -13 ) and extracellular matrix organization ( q- value=10 -4 ) were significantly downregulated. Pro-fibrotic pathways were thus strongly suppressed in Kdm6b deleted foam cells. Analysis of published datasets of foam cells showed that foam cell formation induces these pro-fibrotic characteristics. Overlay of both data sets indicated that fibrotic genes which are induced upon foam cell formation, are reduced in the absence of Kdm6b. These data suggest that foam cell formation induces a pro-fibrotic gene signature in a Kdm6b-dependent manner. Conclusion: We identified Kdm6b as a novel regulator of the pro-fibrotic signature of peritoneal foam cells.

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Anti-Atherosclerotic Activity of (3R)-5-Hydroxymellein from an Endophytic Fungus Neofusicoccum parvum JS-0968 Derived from Vitex rotundifolia through the Inhibition of Lipoproteins Oxidation and Foam Cell Formation

Biomolecules ◽

10.3390/biom10050715 ◽

2020 ◽

Vol 10 (5) ◽

pp. 715

Author(s):

Jae-Yong Kim ◽

Soonok Kim ◽

Sang Hee Shim

Keyword(s):

Conformational Changes ◽

Endophytic Fungus ◽

Foam Cell ◽

Oxidized Ldl ◽

Cell Formation ◽

Density Lipoprotein ◽

Ldl Oxidation ◽

Foam Cell Formation ◽

Macrophage Foam Cell ◽

Neofusicoccum Parvum

An endophytic fungus, Neofusicoccum parvum JS-0968, was isolated from a plant, Vitex rotundifolia. The chemical investigation of its cultures led to the isolation of a secondary metabolite, (3R)-5-hydroxymellein. It has been reported to have antifungal, antibacterial, and antioxidant activity, but there have been no previous reports on the effects of (3R)-5-hydroxymellein on atherosclerosis. The oxidation of lipoproteins and foam cell formation have been known to be significant in the development of atherosclerosis. Therefore, we investigated the inhibitory effects of (3R)-5-hydroxymellein on atherosclerosis through low-density lipoprotein (LDL) and high-density lipoprotein (HDL) oxidation and macrophage foam cell formation. LDL and HDL oxidation were determined by measuring the production of conjugated dienes and malondialdehyde, the amount of hyperchromicity and carbonyl content, conformational changes, and anti-LDL oxidation. In addition, the inhibition of foam cell formation was measured by Oil red O staining. As a result, (3R)-5-hydroxymellein suppressed the oxidation of LDL and HDL through the inhibition of lipid peroxidation, the decrease of negative charges, the reduction of hyperchromicity and carbonyl contents, and the prevention of apolipoprotein A-I (ApoA-I) aggregation and apoB-100 fragmentation. Furthermore, (3R)-5-hydroxymellein significantly reduced foam cell formation induced by oxidized LDL (oxLDL). Taken together, our data show that (3R)-5-hydroxymellein could be a potential preventive agent for atherosclerosis via obvious anti-LDL and HDL oxidation and the inhibition of foam cell formation.

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