scholarly journals Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?

2020 ◽  
Vol 21 (8) ◽  
pp. 2716 ◽  
Author(s):  
Alexander N. Orekhov ◽  
Vasily N. Sukhorukov ◽  
Nikita G. Nikiforov ◽  
Marina V. Kubekina ◽  
Igor A. Sobenin ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Signaling Pathways ◽  
Ldl Receptor ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Cholesterol Accumulation ◽  
Modified Ldl ◽  
Naturally Occurring ◽  
Latex Beads ◽  
Inflammatory Molecules

Accumulation of lipid-laden (foam) cells in the arterial wall is known to be the earliest step in the pathogenesis of atherosclerosis. There is almost no doubt that atherogenic modified low-density lipoproteins (LDL) are the main sources of accumulating lipids in foam cells. Atherogenic modified LDL are taken up by arterial cells, such as macrophages, pericytes, and smooth muscle cells in an unregulated manner bypassing the LDL receptor. The present study was conducted to reveal possible common mechanisms in the interaction of macrophages with associates of modified LDL and non-lipid latex particles of a similar size. To determine regulatory pathways that are potentially responsible for cholesterol accumulation in human macrophages after the exposure to naturally occurring atherogenic or artificially modified LDL, we used transcriptome analysis. Previous studies of our group demonstrated that any type of LDL modification facilitates the self-association of lipoprotein particles. The size of such self-associates hinders their interaction with a specific LDL receptor. As a result, self-associates are taken up by nonspecific phagocytosis bypassing the LDL receptor. That is why we used latex beads as a stimulator of macrophage phagocytotic activity. We revealed at least 12 signaling pathways that were regulated by the interaction of macrophages with the multiple-modified atherogenic naturally occurring LDL and with latex beads in a similar manner. Therefore, modified LDL was shown to stimulate phagocytosis through the upregulation of certain genes. We have identified at least three genes (F2RL1, EIF2AK3, and IL15) encoding inflammatory molecules and associated with signaling pathways that were upregulated in response to the interaction of modified LDL with macrophages. Knockdown of two of these genes, EIF2AK3 and IL15, completely suppressed cholesterol accumulation in macrophages. Correspondingly, the upregulation of EIF2AK3 and IL15 promoted cholesterol accumulation. These data confirmed our hypothesis of the following chain of events in atherosclerosis: LDL particles undergo atherogenic modification; this is accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. This chain of events may explain the relationship between cholesterol accumulation and inflammation. The primary sequence of events in this chain is related to inflammatory response rather than cholesterol accumulation.

scholarly journals Role of Phagocytosis in the Pro-Inflammatory Response in LDL-Induced Foam Cell Formation; a Transcriptome Analysis

2020 ◽  
Vol 21 (3) ◽  
pp. 817 ◽  
Author(s):  
Alexander N. Orekhov ◽  
Nikita G. Nikiforov ◽  
Vasily N. Sukhorukov ◽  
Marina V. Kubekina ◽  
Igor A. Sobenin ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Response ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Master Regulators ◽  
Knock Down ◽  
Modified Ldl ◽  
Naturally Occurring ◽  
Stimulation Of

Excessive accumulation of lipid inclusions in the arterial wall cells (foam cell formation) caused by modified low-density lipoprotein (LDL) is the earliest and most noticeable manifestation of atherosclerosis. The mechanisms of foam cell formation are not fully understood and can involve altered lipid uptake, impaired lipid metabolism, or both. Recently, we have identified the top 10 master regulators that were involved in the accumulation of cholesterol in cultured macrophages induced by the incubation with modified LDL. It was found that most of the identified master regulators were related to the regulation of the inflammatory immune response, but not to lipid metabolism. A possible explanation for this unexpected result is a stimulation of the phagocytic activity of macrophages by modified LDL particle associates that have a relatively large size. In the current study, we investigated gene regulation in macrophages using transcriptome analysis to test the hypothesis that the primary event occurring upon the interaction of modified LDL and macrophages is the stimulation of phagocytosis, which subsequently triggers the pro-inflammatory immune response. We identified genes that were up- or downregulated following the exposure of cultured cells to modified LDL or latex beads (inert phagocytosis stimulators). Most of the identified master regulators were involved in the innate immune response, and some of them were encoding major pro-inflammatory proteins. The obtained results indicated that pro-inflammatory response to phagocytosis stimulation precedes the accumulation of intracellular lipids and possibly contributes to the formation of foam cells. In this way, the currently recognized hypothesis that the accumulation of lipids triggers the pro-inflammatory response was not confirmed. Comparative analysis of master regulators revealed similarities in the genetic regulation of the interaction of macrophages with naturally occurring LDL and desialylated LDL. Oxidized and desialylated LDL affected a different spectrum of genes than naturally occurring LDL. These observations suggest that desialylation is the most important modification of LDL occurring in vivo. Thus, modified LDL caused the gene regulation characteristic of the stimulation of phagocytosis. Additionally, the knock-down effect of five master regulators, such as IL15, EIF2AK3, F2RL1, TSPYL2, and ANXA1, on intracellular lipid accumulation was tested. We knocked down these genes in primary macrophages derived from human monocytes. The addition of atherogenic naturally occurring LDL caused a significant accumulation of cholesterol in the control cells. The knock-down of the EIF2AK3 and IL15 genes completely prevented cholesterol accumulation in cultured macrophages. The knock-down of the ANXA1 gene caused a further decrease in cholesterol content in cultured macrophages. At the same time, knock-down of F2RL1 and TSPYL2 did not cause an effect. The results obtained allowed us to explain in which way the inflammatory response and the accumulation of cholesterol are related confirming our hypothesis of atherogenesis development based on the following viewpoints: LDL particles undergo atherogenic modifications that, in turn, accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. Therefore, it became obvious that the primary event in this sequence is not the accumulation of cholesterol but an inflammatory response.

Master regulators in the foam cell formation; the role of phagocytosis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
V.N Sukhorukov ◽  
Y.V Markina ◽  
A.M Markin ◽  
M Bagheri Ekta ◽  
V.A Khotina ◽  
...  
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Primary Event ◽  
Cholesterol Accumulation ◽  
Master Regulators ◽  
Knock Down ◽  
Modified Ldl ◽  
Naturally Occurring ◽  
Stimulation Of

Abstract Background Foam cell formation caused by modified LDL is the earliest and most noticeable manifestation of atherosclerosis. The mechanisms of foam cell formation are not fully understood and can involve altered lipid uptake, impaired lipid metabolism, or both. 10 inflammation-related master regulators, which were involved in the cholesterol accumulation in cultured macrophages induced by the incubation with modified LDL, have been identified. Objective We hypothesised that the primary event occurring upon the interaction of modified LDL and macrophages is the stimulation of phagocytosis, which subsequently triggers the pro-inflammatory immune response. Methods Cholesterol accumulation was evaluated in primary macrophages with master regulator genes knock-downed by siRNA for either IL15, EIF2AK3, F2RL1, TSPYL2, or ANXA1. Analysis of enriched transcription factor binding sites in promoters of differentially expressed genes and identification of master regulators in the signal transduction network were performed with TRANSFAC and TRANSPATH databases. Results Genes which were up- or downregulated following the exposure of cultured cells to modified LDL or latex beads were determined. Most of the identified master regulators were involved in the innate immune response, and some of them were encoding major pro-inflammatory proteins. Comparative analysis of master regulators revealed similarities in the genetic regulation of the interaction of macrophages with naturally occurring LDL and desialylated LDL. Oxidized and desialylated LDL affected a different spectrum of genes than naturally occurring LDL. These observations suggest that desialylation is the most important modification of LDL occurring in vivo. Thus, modified LDL caused the gene regulation characteristic of the stimulation of phagocytosis. The knock-down of the EIF2AK3 and IL15 genes completely prevented cholesterol accumulation in cultured macrophages, whereas atherogenic naturally occurring LDL caused significant cholesterol accumulation in the control cells. The ANXA1 gene knock-down caused a further decrease in cholesterol content in cultured macrophages. At the same time, knock-down of F2RL1 and TSPYL2 did not cause an effect. Conclusions The results, showing that inflammatory response and the cholesterol accumulation are related, may confirm our hypothesis of atherogenesis development based on the following viewpoints: LDL particles undergo atherogenic modifications that, in turn, accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. Therefore, it became obvious that the primary event in this sequence is not the accumulation of cholesterol but an inflammatory response. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): The Russian Science Foundation

Abstract 1455: Athero-protective Role of IL10 Involves Regulation of Lipid Metabolism in Macrophages

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Xinbing Han ◽  
Shiro Kitamoto ◽  
Qingyu Lian ◽  
William A Boisvert
Keyword(s):  
Lipid Metabolism ◽  
Cholesterol Efflux ◽  
Foam Cell ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Lipid Uptake ◽  
Modified Ldl ◽  
Ldl Uptake ◽  
Inflammatory Molecules

Introduction Previous studies utilizing interleukin (IL)10-overexpressing mice and IL10-deficient mice have demonstrated an anti-atherogenic role of IL10. Internalization of modified low density lipoprotein (LDL) that leads to foam cell formation has long been considered one of the requisite initiating events in atherogenesis. We sought to determine if IL10 exerts its anti-atherogenic effect by modulating lipid metabolism in the macrophage. Methods & results In lipid uptake studies, IL10 substantially stimulated Dil-acetylated (Ac)LDL uptake by 187% in murine macrophage-like RAW264.7 cells. IL10 induced the expression of SR-AII and CD36 by 15.1 fold and 6.5 fold, respectively, in macrophage-derived foam cells. Moreover, CD36 protein levels were increased by IL10, suggesting that these scavenger receptors account, at least in part, for the increase in modified LDL uptake by the macrophages. Accordingly, IL10 treatment for 24hr significantly increased cholesteryl ester content by 1.5 folds compared with untreated controls (p<0.05). Interestingly, IL10 also markedly promoted ATP-binding cassette protein A1 (ABCA1)-mediated free cholesterol efflux to lipid-free apoAI acting as a cholesterol acceptor. This was peroxisome proliferator-activated receptor (PPAR)γ-dependent because specific PPARγ antagonist GW9226 completely blocked the IL10-triggered cholesterol efflux to lipid-free apoAI. In addition, expression of pro-inflammatory molecules such as TNFα, MCP-1 and iCAM-1 was dramatically inhibited by IL10 in the lipid-laden foam cells. Using immunofluorescence assay of caspase 3 fragment and TUNEL assay, we demonstrated that IL10 significantly suppressed apoptosis of foam cells (27.3 ± 2.1% for AcLDL-treated cells vs. 8.3 ± 1.0 %for AcLDL plus IL10-treated cells, n=8). Conclusion Our results indicate that IL10 can mediate both the uptake of cholesterol from modified LDL and the efflux of stored cholesterol. Therefore, IL10 may facilitate the removal of harmful atherogenic lipoprotein molecules from the vessel wall. These characteristics along with its ability to suppress the expression of inflammatory molecules and apoptosis of foam cells make IL10 a highly anti-atherogenic agent.

Abstract 408: Enzyme Modified LDL Induces Migration and Calcification of Human Coronary Artery SMCs

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Bijou Chellan ◽  
Marion Hofmann Bowman
Keyword(s):  
Coronary Artery ◽  
Foam Cell ◽  
Oxidized Ldl ◽  
Control Cell ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Whole Genome ◽  
Human Coronary Artery ◽  
Alizarin Red ◽  
Modified Ldl

Background: Enzyme modified LDL (ELDL) is present in human atherosclerotic lesions and is a major foam cell-forming modified LDL for murine vascular smooth muscle cells (SMC) as reported by us previously. Here we study ELDL and its effects on human coronary artery SMC (HCASMC) in vitro. Methods and Results: Incubation of HCASMC with 10 μg/ml ELDL (trypsin, cholesterol esterase modified) resulted in significant foam cell formation (analyzed by Oil Red O, lipid measurement) compared to HCASMC incubated with oxidized LDL (200 μg/ml; -75%, p<0.01) or native LDL (200 μg/ml; -50%, p<0.01). Whole genome gene expression (Illumina Bead Chip HT12v4, analyzed by DAVID v6.8 and IPA) of HCASMC treated with ELDL, oxLDL, LDL, and control (cell culture medium only) showed several top canonical pathways specifically induced by ELDL, together with activated upstream regulators including p38MAPK, NFkB. ERK. Upregulation of ANGPTL4 and BMP-2 -mRNA (22 and 2 fold respectively over native LDL) was verified by qRT-PCR and immunoblotting. ELDL-induced foam cells showed dose dependent (1-20 μg/ml ELDL) increase in migration in collagen coated trans well dishes, which was attenuated by Lacidepine, a known inhibitor of ELDL uptake in murine SMCs. Furthermore, rANGPTL4 also upregulated HCASMC migration dose dependently (1-5 μg/ml for 24 h) and was comparable with the migration induced by ELDL. However, Lacidipine had no effect on rANGPLT4 mediated migration, suggesting that ANGPLT-4 independently of ELDL uptake promotes migration of HCASMC. In calcification assays using MEM with 0.2% FCS and 1.5 mM phosphate, ELDL at 2.5 μg/ml induced more calcification native LDL (>25%, p<0.01, analyzed by alizarin red staining and organic extraction, and this was proceeded by increase in BMP-2 mRNA. Conclusions: ELDL is highly potent in inducing foam cells in cultured HCASMC. Whole genome expression and bioinformatics analysis indicate up-regulation of pathways linked to osteochondrogenic transformation. BMP-2 and ANGPTL4 are significantly upregulated in ELDL-induced HCASMC foam cells. These results point to the potential of ELDL to induce migratory and osteoblastic effects in HCASMC with potential implications in SMC migration and calcification in human atherosclerosis.

Andrographolide Inhibits Oxidized LDL-Induced Cholesterol Accumulation and Foam Cell Formation in Macrophages

2018 ◽  
Vol 46 (01) ◽  
pp. 87-106 ◽  
Author(s):  
Hung-Chih Lin ◽  
Chong-Kuei Lii ◽  
Hui-Chun Chen ◽  
Ai-Hsuan Lin ◽  
Ya-Chen Yang ◽  
...  
Keyword(s):  
Protein Expression ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Cholesterol Accumulation ◽  
Macrophage Foam Cell ◽  
Macrophage Foam Cells ◽  
Mrna And Protein Expression ◽  
Anti Inflammatory

oxLDL is involved in the pathogenesis of atherosclerotic lesions through cholesterol accumulation in macrophage foam cells. Andrographolide, the bioactive component of Andrographis paniculata, possesses several biological activities such as anti-inflammatory, anti-oxidant, and anticancer functions. Scavenger receptors (SRs), including class A SR (SR-A) and CD36, are responsible for the internalization of oxLDL. In contrast, receptors for reverse cholesterol transport, including ABCA1 and ABCG1, mediate the efflux of cholesterol from macrophage foam cells. Transcription factor liver X receptor [Formula: see text] (LXR[Formula: see text] plays a key role in lipid metabolism and inflammation as well as in the regulation of ABCA1 and ABCG1 expression. Because of the contribution of inflammation to macrophage foam cell formation and the potent anti-inflammatory activity of andrographolide, we hypothesized that andrographolide might inhibit oxLDL-induced macrophage foam cell formation. The results showed that andrographolide reduced oxLDL-induced lipid accumulation in macrophage foam cells. Andrographolide decreased the mRNA and protein expression of CD36 by inducing the degradation of CD36 mRNA; however, andrographolide had no effect on SR-A expression. In contrast, andrographolide increased the mRNA and protein expression of ABCA1 and ABCG1, which were dependent on LXR[Formula: see text]. Andrographolide enhanced LXR[Formula: see text] nuclear translocation and DNA binding activity. Treatment with the LXR[Formula: see text] antagonist GGPP and transfection with LXR[Formula: see text] siRNA reversed the ability of andrographolide to stimulate ABCA1 and ABCG1 protein expression. In conclusion, inhibition of CD36-mediated oxLDL uptake and induction of ABCA1- and ABCG1-dependent cholesterol efflux are two working mechanisms by which andrographolide inhibits macrophage foam cell formation, which suggests that andrographolide could be a potential candidate to prevent atherosclerosis.

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.

scholarly journals Peptide VSAK maintains tissue glucose uptake and attenuates pro-inflammatory responses caused by LPS in an experimental model of the systemic inflammatory response syndrome: a PET study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ismael Luna-Reyes ◽  
Eréndira G. Pérez-Hernández ◽  
Blanca Delgado-Coello ◽  
Miguel Ángel Ávila-Rodríguez ◽  
Jaime Mas-Oliva
Keyword(s):  
Systemic Inflammatory Response Syndrome ◽  
Inflammatory Response ◽  
Glucose Uptake ◽  
Inflammatory Responses ◽  
Serum Levels ◽  
Systemic Inflammatory Response ◽  
Positron Emission ◽  
Inflammatory Molecules ◽  
Circulating Levels ◽  
Lps Treatment

AbstractThe present investigation using Positron Emission Tomography shows how peptide VSAK can reduce the detrimental effects produced by lipopolysaccharides in Dutch dwarf rabbits, used to develop the Systemic Inflammatory Response Syndrome (SIRS). Animals concomitantly treated with lipopolysaccharides (LPS) and peptide VSAK show important protection in the loss of radiolabeled-glucose uptake observed in diverse organs when animals are exclusively treated with LPS. Treatment with peptide VSAK prevented the onset of changes in serum levels of glucose and insulin associated with the establishment of SIRS and the insulin resistance-like syndrome. Treatment with peptide VSAK also allowed an important attenuation in the circulating levels of pro-inflammatory molecules in LPS-treated animals. As a whole, our data suggest that peptide VSAK might be considered as a candidate in the development of new therapeutic possibilities focused on mitigating the harmful effects produced by lipopolysaccharides during the course of SIRS.

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