scholarly journals Decaffeinated coffee and green tea extract inhibit foam cell atherosclerosis by lowering inflammation and improving cholesterol influx/efflux balance through upregulation of PPARγ and miR-155

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 1175
Author(s):  
Ermin Rachmawati ◽  
Mohammad Saifur Rohman ◽  
Djanggan Sargowo ◽  
Umi Kalsum ◽  
Diana Lyrawati ◽  
...  
Keyword(s):  
Green Tea ◽  
Cholesterol Metabolism ◽  
Foam Cell ◽  
Cell Formation ◽  
Green Tea Extract ◽  
Foam Cell Formation ◽  
Cell Numbers ◽  
Decaffeinated Coffee ◽  
Tea Extract ◽  
Pparγ Expression

Background: Foam cells are markers of atherosclerosis and characterise advanced atherosclerotic plaque, stimulated by inflammation caused by high lipid levels in macrophages. The combination of decaffeinated coffee and green tea extract (DCGTE) has been suggested to have a role in foam cell inhibition. Objective: we investigated the inhibiting role of DCGTE against foam cell formation, through modulation of the inflammation process and cholesterol metabolism in macrophage colony stimulating factor- (M-CSF) and oxidized low-density lipoprotein (oxLDL)-exposed macrophages. Methods: Coffee and green tea were extracted by filtration and infusion respectively, and underwent decaffeination using active carbon and blanching methods, respectively. Cells were administered 160/160 and 320/320μg/ml of DCGTE. Foam cell formation was observed using a light microscope after staining with Oil Red O (ORO), and the accumulation of lipids in macrophages with ELISA. Observations of lipid influx and efflux were determined through semiquantitative cluster differentiation 36 (CD36) and ATP binding cassette transporter A1 (ABCA1) expression through immunofluorescence. The inflammation process was quantified using inflammatory/anti-inflammatory markers, e.g., tumor necrosis factor α (TNFα) and interleukin 10 (IL10) with ELISA. Peroxisome proliferator activated response γ (PPARγ) expression and activity were assessed with PCR and ELISA, respectively. The expression of microRNA 155 (miR-155) was examined using qPCR. Results: DCGTE at the above concentrations tended to reduce foam cell numbers, significantly inhibited lipid accumulation (p=0.000), reduced CD36 expression (p=0.000) and TNFα secretion (p=0.000) in Raw264.7 exposed to M-CSF 50ng/ml and oxLDL 50μg/ml.  PPARγ expression (p=0.00) and activity (p=0.001), miR-155 relative expression (p=0.000), and IL10 production (p=0.000) also increased. Conclusion: DCGTE lowered foam cell numbers, possibly through attenuation of the inflammatory process and improvement of lipid/efflux mechanisms in M-CSF and oxLDL-stimulated Raw264.7 cells, via upregulation of PPARγ and miR-155.  Our results suggest DCGTE may help prevent atherosclerosis-based diseases.

scholarly journals Altered PPARγ Expression Promotes Myelin-Induced Foam Cell Formation in Macrophages in Multiple Sclerosis

2020 ◽  
Vol 21 (23) ◽  
pp. 9329
Author(s):  
Elien Wouters ◽  
Elien Grajchen ◽  
Winde Jorissen ◽  
Tess Dierckx ◽  
Suzan Wetzels ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mononuclear Cells ◽  
Foam Cell ◽  
Cell Formation ◽  
Autoimmune Disorder ◽  
Foam Cell Formation ◽  
Peroxisome Proliferator ◽  
Peripheral Blood Mononuclear ◽  
Peroxisome Proliferator Activated Receptors ◽  
Pparγ Expression

Macrophages play a crucial role during the pathogenesis of multiple sclerosis (MS), a neuroinflammatory autoimmune disorder of the central nervous system. Important regulators of the metabolic and inflammatory phenotype of macrophages are liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs). Previously, it has been reported that PPARγ expression is decreased in peripheral blood mononuclear cells of MS patients. The goal of the present study was to determine to what extent PPARγ, as well as the closely related nuclear receptors PPARα and β and LXRα and β, are differentially expressed in monocytes from MS patients and how this change in expression affects the function of monocyte-derived macrophages. We demonstrate that monocytes of relapsing-remitting MS patients display a marked decrease in PPARγ expression, while the expression of PPARα and LXRα/β is not altered. Interestingly, exposure of monocyte-derived macrophages from healthy donors to MS-associated proinflammatory cytokines mimicked this reduction in PPARγ expression. While a reduced PPARγ expression did not affect the inflammatory and phagocytic properties of myelin-loaded macrophages, it did impact myelin processing by increasing the intracellular cholesterol load of myelin-phagocytosing macrophages. Collectively, our findings indicate that an inflammation-induced reduction in PPARγ expression promotes myelin-induced foam cell formation in macrophages in MS.

Prednisone and Its Active Metabolite Prednisolone Attenuate Lipid Accumulation in Macrophages

2019 ◽  
Vol 25 (2) ◽  
pp. 174-186
Author(s):  
Helana Jeries ◽  
Nina Volkova ◽  
Claudia Grajeda-Iglesias ◽  
Mahmoud Najjar ◽  
Mira Rosenblat ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Lipid Accumulation ◽  
Cholesterol Metabolism ◽  
Foam Cell ◽  
Ex Vivo ◽  
Cholesterol Biosynthesis ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Macrophage Foam Cell ◽  
Healthy Human

Background: Synthetic forms of glucocorticoids (GCs; eg, prednisone, prednisolone) are anti-inflammatory drugs that are widely used in clinical practice. The role of GCs in cardiovascular diseases, including atherosclerosis, is highly controversial, and their impact on macrophage foam cell formation is still unknown. We investigated the effects of prednisone and prednisolone on macrophage oxidative stress and lipid metabolism. Methods and Results: C57BL/6 mice were intraperitoneally injected with prednisone or prednisolone (5 mg/kg) for 4 weeks, followed by lipid metabolism analyses in the aorta and peritoneal macrophages. We also analyzed the effect of serum samples obtained from 9 healthy human volunteers before and after oral administration of prednisone (20 mg for 5 days) on J774A.1 macrophage atherogenicity. Finally, J774A.1 macrophages, human monocyte-derived macrophages, and fibroblasts were incubated with increasing concentrations (0-200 ng/mL) of prednisone or prednisolone, followed by determination of cellular oxidative status, and triglyceride and cholesterol metabolism. Prednisone and prednisolone treatment resulted in a significant reduction in triglyceride and cholesterol accumulation in macrophages, as observed in vivo, ex vivo, and in vitro. These effects were associated with GCs’ inhibitory effect on triglyceride- and cholesterol-biosynthesis rates, through downregulation of diacylglycerol acyltransferase 1 and HMG-CoA reductase expression. Glucocorticoid-induced reduction of cellular lipid accumulation was mediated by the GC receptors on the macrophages, because the GC-receptor antagonist (RU486) abolished these effects. In fibroblasts, unlike macrophages, GCs showed no effects. Conclusion: Prednisone and prednisolone exhibit antiatherogenic activity by protecting macrophages from lipid accumulation and foam cell formation.

P4142PI3-kinase delta protects against atherosclerosis progression by governing regulatory T-cell biology

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Zierden ◽  
C Millarg ◽  
S Baldus ◽  
S Rosenkranz ◽  
E M Berghausen ◽  
...  
Keyword(s):  
T Cell ◽  
B Lymphocytes ◽  
Foam Cell ◽  
Cell Formation ◽  
Cd4 T Cell ◽  
Foam Cell Formation ◽  
Atherosclerotic Plaques ◽  
Cell Numbers ◽  
Atherosclerosis Progression

Abstract Introduction and purpose Atherosclerosis is a chronic inflammatory disease of arteries and represents the main underlying cause of death worldwide. Macrophages are major drivers of atherosclerosis by ingestion of lipoproteins, foam cell formation, and secretion of pro-inflammatory mediators. Although macrophages outnumber other leukocytes in atherosclerotic plaques, T and B lymphocytes can shape the course of disease by promoting or mitigating inflammatory responses. Leukocytes highly express the phosphoinositide 3-kinase isoform delta (PI3Kd), exerting a key role in the regulation of immune responses including the activation, proliferation, differentiation, and effector function of lymphocytes. Since macrophages and lymphocytes are all major effectors of atherosclerosis, we aimed to understand the role of PI3Kd in these leukocytes during atherogenesis. Methods and results To investigate the role of haematopoietic PI3Kd in atherosclerosis, bone marrow from PI3Kd−/− or PI3Kd+/+ mice was transplanted into LDLR−/− mice. After 6 weeks of feeding on an atherogenic diet, PI3Kd−/− recipient LDLR−/− mice displayed significantly impaired CD4+ and CD8+ T-cell numbers, CD4+ T-cell activation, CD4+ effector T cells, and proatherogenic CD4+ T helper (Th) 1 responses in para-aortic lymph nodes and spleen compared with PI3Kd+/+ transplanted controls. Surprisingly, the net effect of PI3Kd deficiency was a substantial increase of aortic inflammation and atherosclerosis in LDLR−/− mice. Moreover, haematopoietic PI3Kd deficiency augmented macrophage accumulation in atherosclerotic plaques of LDLR−/− mice, whereas major macrophage functions including foam cell formation, efferocytosis, and cytokine secretion were unaffected by PI3Kd inactivation in these phagocytes. However, haematopoietic PI3Kd deficiency led to depletion of atheroprotective B-1 cells and reduction of proatherogenic B-2 cells in LDLR−/− mice. Moreover, haematopoietic PI3Kd deficiency caused a significant reduction of regulatory CD4+ T cells (Tregs) in plaques, para-aortic lymph nodes, and spleen of LDLR−/− mice. Furthermore, PI3Kd−/− Tregs exhibited reduced secretion of anti-inflammatory cytokines IL-10 and TGF-b as well as impaired suppression of CD4+ T-cell proliferation. Consequently, adoptive transfer of PI3Kd+/+ Tregs fully constrains the atherosclerotic burden in PI3Kd−/− transplanted LDLR−/− mice without affecting B cell numbers. Conclusions We demonstrate that PI3Kd plays a crucial role in B lymphocytes, Th1 cells, and Tregs during atherogenesis. Lack of PI3Kd signalling in atheroprotective Treg responses outplays its impact on proatherogenic Th1 responses, thus leading to aggravated atherosclerosis. Hence, PI3Kd is a key regulator of Treg biology and thereby protects against atherosclerosis progression. Acknowledgement/Funding Center for Molecular Medicine Cologne (CMMC) and the Marga and Walter Boll-Stiftung

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

2016 ◽  
Vol 64 (16) ◽  
pp. 3186-3195 ◽  
Author(s):  
Shih-Hsin Tu ◽  
Ming-Yao Chen ◽  
Li-Ching Chen ◽  
Yi-Ting Mao ◽  
Chi-Hou Ho ◽  
...  
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Mechanistic Study ◽  
Foam Cell Formation ◽  
Tea Extract

Haematopoietic PI3-kinase delta deficiency profoundly impairs regulatory T-cell biology and thereby protection against atherosclerosis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Zierden ◽  
C Millarg ◽  
E.M Berghausen ◽  
L Feik ◽  
S Baldus ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Funding Source ◽  
Cell Numbers

Abstract Introduction and purpose Atherosclerosis is a chronic inflammatory disease of arteries, critically involving leukocytes like macrophages as well as T and B lymphocytes. Macrophages are major drivers of disease through the ingestion of lipoproteins, foam cell formation, and secretion of inflammatory mediators. Although macrophages outnumber other leukocytes in atherosclerotic plaques, T and B cells can shape the course of disease by promoting or mitigating inflammatory responses. Leukocytes highly express the phosphoinositide 3-kinase isoform delta (PI3Kd), exerting a key role in the regulation of immune responses including activation, proliferation, differentiation, and effector functions. Therefore, PI3Kd represents a promising target for the modulation of inflammatory diseases. Consequently, we aimed to analyse the role of PI3Kd in leukocytes during atherogenesis. Methods and results To investigate the role of PI3Kd in atherosclerosis, bone marrow from PI3Kd−/− or PI3Kd+/+ mice was transplanted into LDLR−/− mice. After a 6-weeks-challenge by high fat diet, PI3Kd−/− recipient LDLR−/− mice displayed profoundly impaired CD4+ and CD8+ T-cell numbers, CD4+ T-cell activation, CD4+ effector T-cell differentiation, and proatherogenic CD4+ T-helper (Th) 1 responses in para-aortic lymph nodes and spleen compared with PI3Kd+/+ transplanted controls. Surprisingly, the net effect of PI3Kd deficiency was a substantial increase of aortic inflammation and atherosclerosis in LDLR−/− mice. Whereas plaque content and functions of macrophages including foam cell formation, efferocytosis, and cytokine secretion remained unaffected, haematopoietic PI3Kd ablation strongly reduced mature B cells and serum immunoglobulins in LDLR−/− mice. Importantly, PI3Kd deficiency severely impaired numbers and immunosuppressive functions of regulatory CD4+ T cells (Tregs) in spleen, para-aortic lymph nodes, and plaques of LDLR−/− mice. Consequently, adoptive transfer of PI3Kd+/+ Tregs fully constrained the plaque burden in PI3Kd−/− transplanted LDLR−/− mice without affecting B-cell numbers and serum immunoglobulins, whereas adoptively transferred PI3Kd−/− Tregs were unable to relieve atherosclerosis progression. Conclusions Here, we demonstrate that PI3Kd plays a crucial role in Tregs, Th1 cells, and B cells during atherogenesis. Lack of PI3Kd signalling specifically in atheroprotective Treg responses outplays its impact on proatherogenic Th1 and B-cell responses, thus leading to aggravated atherosclerosis. Hence, PI3Kd is a key regulator of Treg biology and thereby protects against atherosclerosis. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Marga and Walter Boll Foundation

Desmosterol suppresses macrophage inflammasome activation and protects against vascular inflammation and atherosclerosis

2021 ◽  
Vol 118 (47) ◽  
pp. e2107682118
Author(s):  
Xinbo Zhang ◽  
Jeffrey G. McDonald ◽  
Binod Aryal ◽  
Alberto Canfrán‐Duque ◽  
Emily L. Goldberg ◽  
...  
Keyword(s):  
Cholesterol Metabolism ◽  
Foam Cell ◽  
Cell Formation ◽  
Cholesterol Homeostasis ◽  
Foam Cell Formation ◽  
Inflammasome Activation ◽  
Human Coronary Artery ◽  
Macrophage Foam Cell ◽  
Critical Function

Cholesterol biosynthetic intermediates, such as lanosterol and desmosterol, are emergent immune regulators of macrophages in response to inflammatory stimuli or lipid overloading, respectively. However, the participation of these sterols in regulating macrophage functions in the physiological context of atherosclerosis, an inflammatory disease driven by the accumulation of cholesterol-laden macrophages in the artery wall, has remained elusive. Here, we report that desmosterol, the most abundant cholesterol biosynthetic intermediate in human coronary artery lesions, plays an essential role during atherogenesis, serving as a key molecule integrating cholesterol homeostasis and immune responses in macrophages. Depletion of desmosterol in myeloid cells by overexpression of 3β-hydroxysterol Δ24-reductase (DHCR24), the enzyme that catalyzes conversion of desmosterol to cholesterol, promotes the progression of atherosclerosis. Single-cell transcriptomics in isolated CD45+CD11b+ cells from atherosclerotic plaques demonstrate that depletion of desmosterol increases interferon responses and attenuates the expression of antiinflammatory macrophage markers. Lipidomic and transcriptomic analysis of in vivo macrophage foam cells demonstrate that desmosterol is a major endogenous liver X receptor (LXR) ligand involved in LXR/retinoid X receptor (RXR) activation and thus macrophage foam cell formation. Decreased desmosterol accumulation in mitochondria promotes macrophage mitochondrial reactive oxygen species production and NLR family pyrin domain containing 3 (NLRP3)–dependent inflammasome activation. Deficiency of NLRP3 or apoptosis-associated speck-like protein containing a CARD (ASC) rescues the increased inflammasome activity and atherogenesis observed in desmosterol-depleted macrophages. Altogether, these findings underscore the critical function of desmosterol in the atherosclerotic plaque to dampen inflammation by integrating with macrophage cholesterol metabolism and inflammatory activation and protecting from disease progression.

scholarly journals PAK1 Silencing Attenuated Proinflammatory Macrophage Activation and Foam Cell Formation by Increasing PPARγ Expression

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Wen-Lin Cheng ◽  
Quan Zhang ◽  
Bo Li ◽  
Jian-Lei Cao ◽  
Lin Jiao ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Foam Cell ◽  
Macrophage Polarization ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
M2 Macrophage ◽  
Macrophage Phenotype ◽  
Loss Of Function ◽  
M1 Macrophage ◽  
Pparγ Expression

Macrophage polarization in response to environmental cues has emerged as an important event in the development of atherosclerosis. Compelling evidences suggest that P21-activated kinases 1 (PAK1) is involved in a wide variety of diseases. However, the potential role and mechanism of PAK1 in regulation of macrophage polarization remains to be elucidated. Here, we observed that PAK1 showed a dramatically increased expression in M1 macrophages but decreased expression in M2 macrophages by using a well-established in vitro model to study heterogeneity of macrophage polarization. Adenovirus-mediated loss-of-function approach demonstrated that PAK1 silencing induced an M2 macrophage phenotype-associated gene profiles but repressed the phenotypic markers related to M1 macrophage polarization. Additionally, dramatically decreased foam cell formation was found in PAK1 silencing-induced M2 macrophage activation which was accompanied with alternation of marker account for cholesterol efflux or influx from macrophage foam cells. Moderate results in lipid metabolism and foam cell formation were found in M1 macrophage activation mediated by AdshPAK1. Importantly, we presented mechanistic evidence that PAK1 knockdown promoted the expression of PPARγ, and the effect of macrophage activation regulated by PAK1 silencing was largely reversed when a PPARγ antagonist was utilized. Collectively, these findings reveal that PAK1 is an independent effector of macrophage polarization at least partially attributed to regulation of PPARγ expression, which suggested PAK1-PPARγ axis as a novel therapeutic strategy in atherosclerosis management.

scholarly journals TMT-based quantitative proteomic profiling of human monocyte-derived macrophages and foam cells

2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Yali Zhang ◽  
Yu Fu ◽  
Linying Jia ◽  
Chenyang Zhang ◽  
Wenbin Cao ◽  
...  
Keyword(s):  
Immune Response ◽  
Endoplasmic Reticulum ◽  
Protein Interaction ◽  
Cholesterol Metabolism ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Differentially Expressed Proteins ◽  
Related Proteins

Abstract Background Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide, most of which are caused by atherosclerosis. Discerning processes that participate in macrophage-to-foam cell formation are critical for understanding the basic mechanisms underlying atherosclerosis. To explore the molecular mechanisms of foam cell formation, differentially expressed proteins were identified. Methods Human peripheral blood mononuclear cells were stimulated with macrophage colony-stimulating factor, and obtained macrophages were transformed into foam cells by oxidized low-density lipoprotein. Tandem mass tag (TMT) labeling combined with mass spectrometry was performed to find associations between foam cell transformation and proteome profiles. Results Totally, 5146 quantifiable proteins were identified, among which 1515 and 182 differentially expressed proteins (DEPs) were found in macrophage/monocyte and foam cell/macrophage, respectively. Subcellular localization analysis revealed that downregulated DEPs of macrophages/monocytes were mostly located in the nucleus, whereas upregulated DEPs of foam cells/macrophages were mostly extracellular or located in the plasma membrane. Functional analysis of DEPs demonstrated that cholesterol metabolism-related proteins were upregulated in foam cells, whereas immune response-related proteins were downregulated in foam cells. The protein interaction network showed that the DEPs with the highest interaction scores between macrophages and foam cells were mainly concentrated in lysosomes and the endoplasmic reticulum. Conclusions Proteomics analysis suggested that cholesterol metabolism was upregulated, while the immune response was suppressed in foam cells. KEGG enrichment analysis and protein-protein interaction analysis indicated that DEPs located in the endoplasmic reticulum and lysosomes might be key drivers of foam cell formation. These data provide a basis for identifying the potential proteins associated with the molecular mechanism underlying macrophage transformation to foam cells.

EM of human atherosclerosis: Aortic fatty streaks with transitional lesion features

1992 ◽  
Vol 50 (1) ◽  
pp. 622-623
Author(s):  
K. Florian Klemp ◽  
J.R. Guyton
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Processing Technique ◽  
Foam Cell Formation ◽  
Tissue Preparation ◽  
Electron Microscopic ◽  
Extracellular Lipid ◽  
Electron Microscopic Cytochemistry ◽  
Human Atherosclerosis ◽  
Clinically Significant

The earliest distinctive lesions in human atherosclerosis are fatty streaks (FS), characterized initially by lipid-laden foam cell formation. Fibrous plaques (FP), the clinically significant lesions, differ from FS in several respects. In addition to foam cells, the FP also exhibit fibromuscular proliferation and a necrotic core region rich in extracellular lipid. The possible transition of FS into mature FP has long been debated, however. A subset of FS described by Katz etal., was intermediate in lipid composition between ordinary FS and FP. We investigated this hypothesis by electron microscopic cytochemistry by employing a tissue processing technique previously described by our laboratory. Osmium-tannic acid-paraphenylenediamine (OTAP) tissue preparation enabled ultrastructural analysis of lipid deposits to discern features characteristic of mature fibrous plaques.

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