scholarly journals The Potential of Fluocinolone Acetonide to Mitigate Inflammation and Lipid Accumulation in 2D and 3D Foam Cell Cultures

2018 ◽  
Vol 2018 ◽  
pp. 1-11
Author(s):  
Luong T. H. Nguyen ◽  
Aristo Muktabar ◽  
Jinkai Tang ◽  
Yee Shan Wong ◽  
Colby S. Thaxton ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cells ◽  
Fluocinolone Acetonide ◽  
Major Adverse Cardiovascular Events ◽  
Foam Cell Formation ◽  
Fetal Bovine ◽  
Atherosclerosis Development ◽  
2D And 3D

Inflammation plays an important role in all stages of atherosclerosis development. Therefore, the use of anti-inflammatory drugs could reduce the risk of major adverse cardiovascular events due to atherosclerosis. Herein, we explored the capacity of fluocinolone acetonide (FA), a glucocorticoid (GC), in modulating foam cell formation and response. Human THP-1 derived foam cells were produced using 100 μg/mL oxidized low-density lipoproteins (OxLDL) and fetal bovine serum (1 and 10%). 2D cultures of these cells were treated with FA (0.1, 1, 10, and 50 μg/mL) in comparison with dexamethasone (Dex). Results showed that treatment with 0.1 and 1 μg/mL FA and Dex improved foam cell survival. FA and Dex also inhibited inflammatory cytokine (CD14, M-CSF, MIP-3α, and TNF-α) secretion. Notably, at the concentration of 1 μg/mL, both FA and Dex reduced cholesteryl ester accumulation. Compared to Dex, FA was significantly better in reducing lipid accumulation at the therapeutic concentrations of 1 and 10 μg/mL. In a novel 3D foam cell spheroid model, FA was shown to be more effective than Dex in diminishing lipid accumulation, at the concentration of 0.1 μg/mL. Taken together, FA was demonstrated to be effective in preventing both lipid accumulation and inflammation in foam cells.

scholarly journals Macrophages and Foam Cells: Brief Overview of Their Role, Linkage, and Targeting Potential in Atherosclerosis

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1221
Author(s):  
Anastasia V. Poznyak ◽  
Nikita G. Nikiforov ◽  
Antonina V. Starodubova ◽  
Tatyana V. Popkova ◽  
Alexander N. Orekhov
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Foam Cells ◽  
Cardiovascular Complications ◽  
Foam Cell Formation ◽  
Therapeutic Approaches ◽  
Promising Target ◽  
Life Threatening ◽  
Atherosclerosis Development

Atherosclerosis is still one of the main causes of death around the globe. This condition leads to various life-threatening cardiovascular complications. However, no effective preventive measures are known apart from lifestyle corrections, and no cure has been developed. Despite numerous studies in the field of atherogenesis, there are still huge gaps in already poor understanding of mechanisms that underlie the disease. Inflammation and lipid metabolism violations are undoubtedly the key players, but many other factors, such as oxidative stress, endothelial dysfunction, contribute to the pathogenesis of atherosclerosis. This overview is focusing on the role of macrophages in atherogenesis, which are at the same time a part of the inflammatory response, and also tightly linked to the foam cell formation, thus taking part in both crucial for atherogenesis processes. Being essentially involved in atherosclerosis development, macrophages and foam cells have attracted attention as a promising target for therapeutic approaches.

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.

scholarly journals Foam Cells as Therapeutic Targets in Atherosclerosis with a Focus on the Regulatory Roles of Non-Coding RNAs

2021 ◽  
Vol 22 (5) ◽  
pp. 2529
Author(s):  
Amin Javadifar ◽  
Sahar Rastgoo ◽  
Maciej Banach ◽  
Tannaz Jamialahmadi ◽  
Thomas P. Johnston ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Special Focus ◽  
Lipid Uptake ◽  
Therapeutic Goals ◽  
Expression Of Genes

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.

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

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.

scholarly journals Signaling Pathways and Key Genes Involved in Regulation of foam Cell Formation in Atherosclerosis

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 584 ◽  
Author(s):  
Anastasia V. Poznyak ◽  
Wei-Kai Wu ◽  
Alexandra A. Melnichenko ◽  
Reinhard Wetzker ◽  
Vasily Sukhorukov ◽  
...  
Keyword(s):  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Beneficial Effects ◽  
Complex Process ◽  
Experimental Therapies ◽  
Inflammatory Drugs

Atherosclerosis is associated with acute cardiovascular conditions, such as ischemic heart disease, myocardial infarction, and stroke, and is the leading cause of morbidity and mortality worldwide. Our understanding of atherosclerosis and the processes triggering its initiation is constantly improving, and, during the last few decades, many pathological processes related to this disease have been investigated in detail. For example, atherosclerosis has been considered to be a chronic inflammation triggered by the injury of the arterial wall. However, recent works showed that atherogenesis is a more complex process involving not only the immune system, but also resident cells of the vessel wall, genetic factors, altered hemodynamics, and changes in lipid metabolism. In this review, we focus on foam cells that are crucial for atherosclerosis lesion formation. It has been demonstrated that the formation of foam cells is induced by modified low-density lipoprotein (LDL). The beneficial effects of the majority of therapeutic strategies with generalized action, such as the use of anti-inflammatory drugs or antioxidants, were not confirmed by clinical studies. However, the experimental therapies targeting certain stages of atherosclerosis, among which are lipid accumulation, were shown to be more effective. This emphasizes the relevance of future detailed investigation of atherogenesis and the importance of new therapies development.

Pomegranate peel polyphenols inhibit lipid accumulation and enhance cholesterol efflux in raw264.7 macrophages

2016 ◽  
Vol 7 (7) ◽  
pp. 3201-3210 ◽  
Author(s):  
Shengjuan Zhao ◽  
Jianke Li ◽  
Lifang Wang ◽  
Xiaoxia Wu
Keyword(s):  
Lipid Accumulation ◽  
Cholesterol Efflux ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Pomegranate Peel ◽  
Raw264.7 Macrophages

Pomegranate peel polyphenols hindered ox-LDL-induced raw264.7 foam cell formation, by decreasing CD36 and promoting ABCA1 and LXRα expression.

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.

scholarly journals Quercetin Suppresses the Progression of Atherosclerosis by Regulating MST1-Mediated Autophagy in ox-LDL-Induced RAW264.7 Macrophage Foam Cells

2019 ◽  
Vol 20 (23) ◽  
pp. 6093 ◽  
Author(s):  
Hui Cao ◽  
Qingling Jia ◽  
Li Yan ◽  
Chuan Chen ◽  
Sanli Xing ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
Foam Cell ◽  
Cell Model ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Raw264.7 Macrophages ◽  
Age Related ◽  
Raw264.7 Macrophage ◽  
Senescence Phenotype

Objective: To investigate the process by which quercetin suppresses atherosclerosis by upregulating MST1-mediated autophagy in RAW264.7 macrophages. Methods: An in vitro foam cell model was established by culturing RAW264.7 macrophages with oxidized low-density lipoprotein (ox-LDL). The cells were treated with quercetin alone or in combination with the autophagy inhibitor, 3-methyladenine, and autophagy agonist, rapamycin. Cell viability was detected with a CCK-8 kit. Lipid accumulation was detected by oil red O staining, senescence was detected by SA-β-gal (senescence-associated β-galactosidase) staining, reactive oxygen species were detected by ROS assay kit. Autophagosomes and mitochondria were detected by transmission electron microscope (TEM), and expression of MST1, LC3-II/I, Beclin1, Bcl-2, P21, and P16 were detected by immunofluorescence and Western blot. Results: Ox-LDL induced RAW264.7 macrophage-derived foam cell formation, reduced survival, aggravated cell lipid accumulation, and induced a senescence phenotype. This was accompanied by decreased formation of autophagosome; increased expression of P53, P21, and P16; and decreased expression of LC3-II/I and Beclin1. After intervention with quercetin, the cell survival rate was increased, and lipid accumulation and senescence phenotype were reduced. Furthermore, the expression of LC3-II/I and Beclin1 were increased, which was consistent with the ability of quercetin to promote autophagy. Ox-LDL also increased the expression of MST1, and this increase was blocked by quercetin, which provided a potential mechanism by which quercetin may protect foam cells against age-related detrimental effects. Conclusion: Quercetin can inhibit the formation of foam cells induced by ox-LDL and delay senescence. The mechanism may be related to the regulation of MST1-mediated autophagy of RAW264.7 cells.

Abstract 570: Macrophage Catabolism of Aggregated Lipoproteins Using a Novel Extracellular Compartment Regulates Lipid Accumulation During Atherosclerosis

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Rajesh K Singh ◽  
Abigail S Haka ◽  
Valeria C Barbosa-Lorenzi ◽  
Arky Asmal ◽  
Frederik Lund ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
Actin Polymerization ◽  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Atherosclerotic Vascular Disease ◽  
Extracellular Compartment

Despite impressive advances in research, prevention, and treatment, atherosclerotic vascular disease remains the leading cause of death in the developed world. Mechanisms of cholesterol accumulation in the arteries have been studied intensively, but the in vivo contributions of different pathways leading to lipid accumulation and foam cell formation are not understood. In the arteries, low-density lipoprotein (LDL) is aggregated and bound to the extracellular matrix. When such aggregated LDL is presented to macrophages, they form a novel acidic, hydrolytic compartment that is topologically extracellular, to which lysosomal enzymes are secreted. Such compartments are observed in vivo in murine atherosclerotic plaque macrophages interacting with cholesterol rich deposits. Using state-of-the-art quantitative and high resolution microscopy techniques, characterization of compartment morphology reveals how macrophages use local actin polymerization to drive plasma membrane remodeling at the interface with aggregated LDL. This leads to sequestration of aggregated LDL into topologically convoluted structures that allow acidification, catabolism and internalization of LDL. We find that a TLR4/MyD88/Syk/PI3 kinase/Akt dependent signaling pathway in macrophages regulates the formation of such catabolic compartments. Consistent with this, deficiency of TLR4 in vivo can protect macrophages from lipid accumulation in murine atherosclerotic plaques. Herein, we provide compelling evidence for a novel form of catabolism that macrophages use to degrade aggregated LDL in vivo during atherosclerosis and this process leads to foam cell formation, cell death and promotes disease progression.

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