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.

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 Epac1 (Exchange Protein Directly Activated by cAMP 1) Upregulates LOX-1 (Oxidized Low-Density Lipoprotein Receptor 1) to Promote Foam Cell Formation and Atherosclerosis Development

2020 ◽  
Vol 40 (12) ◽  
Author(s):  
William G. Robichaux ◽  
Fang C. Mei ◽  
Wenli Yang ◽  
Hui Wang ◽  
Hua Sun ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Low Density ◽  
Lipid Uptake ◽  
Wild Type ◽  
Ldl Uptake ◽  
Atherosclerosis Development

Objective: The cAMP second messenger system, a major stress-response pathway, plays essential roles in normal cardiovascular functions and in pathogenesis of heart diseases. Here, we test the hypothesis that the Epac1 (exchange protein directly activated by cAMP 1) acts as a major downstream effector of cAMP signaling to promote atherogenesis and represents a novel therapeutic target. Approach and Results: To ascertain Epac1’s function in atherosclerosis development, a triple knockout mouse model ( LTe ) was generated by crossing Epac1 −/− mice with atherosclerosis-prone LDb mice lacking both Ldlr and Apobec1 . Deletion of Epac1 led to a significant reduction of atherosclerotic lesion formation as measured by postmortem staining, accompanied by attenuated macrophage/foam cell infiltrations within atherosclerotic plaques as determined by immunofluorescence staining in LTe animals compared with LDb littermates. Primary bone marrow–derived macrophages were isolated from Epac1-null and wild-type mice to investigate the role of Epac1 in lipid uptake and foam cell formation. ox-LDLs (oxidized low-density lipoproteins) stimulation of bone marrow–derived macrophages led to elevated intracellular cAMP and Epac1 levels, whereas an Epac-specific agonist, increased lipid accumulation in wild-type, but not Epac1-null, bone marrow–derived macrophages. Mechanistically, Epac1 acts through PKC (protein kinase C) to upregulate LOX-1 (ox-LDL receptor 1), a major scavenger receptor for ox-LDL uptake, exerting a feedforward mechanism with ox-LDL to increase lipid uptake and propel foam cell formation and atherogenesis. Conclusions: Our study demonstrates a fundamental role of cAMP/Epac1 signaling in vascular remodeling by promoting ox-LDL uptake and foam cell formation during atherosclerosis lesion development. Therefore, Epac1 represents a promising, unexplored therapeutic target for atherosclerosis.

scholarly journals Swiprosin-1 deficiency in macrophages alleviated atherogenesis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ling-Chang Tong ◽  
Zhi-Bin Wang ◽  
Jia-Qi Zhang ◽  
Yue Wang ◽  
Wei-Ye Liu ◽  
...  
Keyword(s):  
Foam Cell ◽  
Atherosclerotic Lesion ◽  
Foam Cell Formation ◽  
High Cholesterol Diet ◽  
Atherosclerotic Plaques ◽  
Inflammatory Factor ◽  
Lipid Uptake ◽  
Wild Type ◽  
Raw264.7 Macrophages

AbstractMacrophages play a vital role in the development of atherosclerosis. Previously, we have found that swiprosin-1 was abundantly expressed in macrophages. Here, we investigated the role of swiprosin-1 expressed in macrophages in atherogenesis. Bone marrow transplantation was performed from swiprosin-1-knockout (Swp−/−) mice and age-matched ApoE−/− mice. Atherosclerotic lesion, serum lipid, and interleukin-β (IL-β) levels were detected. In vitro, the peritoneal macrophages isolated from Swp−/− and wild-type mice were stimulated with oxidized low-density lipoprotein (ox-LDL) and the macrophage of foam degree, cellular lipid content, apoptosis, inflammatory factor, migration, and autophagy were determined. Our results showed that swiprosin-1 was mainly expressed in macrophages of atherosclerotic plaques in aorta from ApoE−/− mice fed with high-cholesterol diet (HCD). The expression of swiprosin-1 in the foaming of RAW264.7 macrophages gradually increased with the increase of the concentration and time stimulated with ox-LDL. Atherosclerotic plaques, accumulation of macrophages, collagen content, serum total cholesterol, LDL, and IL-β levels were decreased in Swp−/− → ApoE−/− mice compared with Swp+/+ → ApoE−/− mice fed with HCD for 16 weeks. The macrophage foam cell formation and cellular cholesterol accumulation were reduced, while the lipid uptake and efflux increased in macrophages isolated from Swp−/− compared to wild-type mice treated with ox-LDL. Swiprosin-1 deficiency in macrophages could inhibit apoptosis, inflammation, migration, and promote autophagy. Taken together, our results demonstrated that swiprosin-1 deficiency in macrophages could alleviate the development and progression of AS. The role of swiprosin-1 may provide a promising new target for ameliorating AS.

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.

Macrophage-Specific IGF-1 Overexpression Reduces CXCL12 Chemokine Levels and Suppresses Atherosclerotic Burden in Apoe-Deficient Mice

2021 ◽  
Author(s):  
Patricia Snarski ◽  
Sergiy Sukhanov ◽  
Tadashi Yoshida ◽  
Yusuke Higashi ◽  
Svitlana Danchuk ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Cholesterol Efflux ◽  
Foam Cell ◽  
Foam Cells ◽  
Peritoneal Macrophages ◽  
Cellular Growth ◽  
Foam Cell Formation ◽  
Atherosclerotic Burden ◽  
Lipid Efflux ◽  
Deficient Mice

Objective: IGF-1 (insulin-like growth factor 1) exerts pleiotropic effects including promotion of cellular growth, differentiation, survival, and anabolism. We have shown that systemic IGF-1 administration reduced atherosclerosis in Apoe −/ − (apolipoprotein E deficient) mice, and this effect was associated with a reduction in lesional macrophages and a decreased number of foam cells in the plaque. Almost all cell types secrete IGF-1, but the effect of macrophage-derived IGF-1 on the pathogenesis of atherosclerosis is poorly understood. We hypothesized that macrophage-derived IGF-1 will reduce atherosclerosis. Approach and Results: We created macrophage-specific IGF-1 overexpressing mice on an Apoe − / − background. Macrophage-specific IGF-1 overexpression reduced plaque macrophages, foam cells, and atherosclerotic burden and promoted features of stable atherosclerotic plaque. Macrophage-specific IGF1 mice had a reduction in monocyte infiltration into plaque, decreased expression of CXCL12 (CXC chemokine ligand 12), and upregulation of ABCA1 (ATP-binding cassette transporter 1), a cholesterol efflux regulator, in atherosclerotic plaque and in peritoneal macrophages. IGF-1 prevented oxidized lipid-induced CXCL12 upregulation and foam cell formation in cultured THP-1 macrophages and increased lipid efflux. We also found an increase in cholesterol efflux in macrophage-specific IGF1–derived peritoneal macrophages. Conclusions: Macrophage IGF-1 overexpression reduced atherosclerotic burden and increased features of plaque stability, likely via a reduction in CXCL12-mediated monocyte recruitment and an increase in ABCA1-dependent macrophage lipid efflux.

scholarly journals Myeloid-specific deficiency of pregnane X receptor decreases atherosclerosis in LDL receptor-deficient mice

2020 ◽  
Vol 61 (5) ◽  
pp. 696-706
Author(s):  
Yipeng Sui ◽  
Zhaojie Meng ◽  
Se-Hyung Park ◽  
Weiwei Lu ◽  
Christopher Livelo ◽  
...  
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Ldl Receptor ◽  
Plasma Lipid ◽  
Pregnane X Receptor ◽  
Foam Cell Formation ◽  
Lipid Uptake ◽  
Atherosclerosis Development

The pregnane X receptor (PXR) is a nuclear receptor that can be activated by numerous drugs and xenobiotic chemicals. PXR thereby functions as a xenobiotic sensor to coordinately regulate host responses to xenobiotics by transcriptionally regulating many genes involved in xenobiotic metabolism. We have previously reported that PXR has pro-atherogenic effects in animal models, but how PXR contributes to atherosclerosis development in different tissues or cell types remains elusive. In this study, we generated an LDL receptor-deficient mouse model with myeloid-specific PXR deficiency (PXRΔMyeLDLR−/−) to elucidate the role of macrophage PXR signaling in atherogenesis. The myeloid PXR deficiency did not affect metabolic phenotypes and plasma lipid profiles, but PXRΔMyeLDLR−/− mice had significantly decreased atherosclerosis at both aortic root and brachiocephalic arteries compared with control littermates. Interestingly, the PXR deletion did not affect macrophage adhesion and migration properties, but reduced lipid accumulation and foam cell formation in the macrophages. PXR deficiency also led to decreased expression of the scavenger receptor CD36 and impaired lipid uptake in macrophages of the PXRΔMyeLDLR−/− mice. Further, RNA-Seq analysis indicated that treatment with a prototypical PXR ligand affects the expression of many atherosclerosis-related genes in macrophages in vitro. These findings reveal a pivotal role of myeloid PXR signaling in atherosclerosis development and suggest that PXR may be a potential therapeutic target in atherosclerosis management.

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 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.

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