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 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.

Abstract 306: Deficiency of ROCK1 in Macrophages Protects Against Atherosclerosis

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Hong-Wei Wang ◽  
Naotsugu Oyama ◽  
Yoshiyuki Rikitake ◽  
Shiro Kitamoto ◽  
Jonathan Gitlin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Foam Cell ◽  
Vascular Inflammation ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Low Density ◽  
Lipid Uptake

Background: Rho kinases (ROCKs) are serine-threonine protein kinases that regulate various cellular functions. There is increasing evidence that the RhoA/ROCK pathway plays an important pathophysiological role in cardiovascular diseases. However, direct evidence of which ROCK isoforms or target tissues are involved in the atherogenic process is still lacking. Objective: The aim of this study was to determine the effect of ROCK1 deficiency on atherogenesis and how ROCK1 affects key atherosclerosis-related macrophage function such as lipid uptake and chemotaxis. Methods: We utilized ROCK1 −/− mice and the atherosclerosis-prone apolipoprotein E knockout (apoE −/− ) mice or low-density lipoprotein receptor knockout (LDLR −/− ) mice to investigate the role of ROCK1 in the pathogenesis of atherosclerotic plaque formation. Bone marrow-derived macrophages from ROCK1 −/− and ROCK1 +/+ mice were used to investigate acetylated (Ac)LDL-mediated foam cell formation and chemotaxis. Results: Compared to atherosclerosis-prone apoE −/− mice, apoE −/− ROCK1 +/− mice had substantially less fatty streaks foam cells and atherosclerosis (77.0 ± 12.9 × 10 3 μm 2 versus 166.4 ± 14.6 × 10 3 μm 2 , P < 0.01). Atherosclerotic lesions were reduced also in LDLR −/− mice, whose bone marrow were replaced with bone marrow derived from ROCK1 −/− mice compared to ROCK1 +/+ recipients (181.5 ± 15.6 × 10 3 μm 2 versus 448.5 ± 33.3 × 10 3 μm 2 , P < 0.05). Bone marrow-derived ROCK1-deficient macrophages exhibited impaired chemotaxis to monocyte chemotactic protein-1 and showed reduced ability to take up lipids and to develop into foam cells when exposed to modified low density lipoprotein. Conclusion: These findings indicate that ROCK1 in macrophages is a critical mediator of foam cell formation, macrophage chemotaxis and atherogenesis, and suggest that macrophage ROCK1 may be an important therapeutic target for vascular inflammation and 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 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 TLR4-dependent signaling drives extracellular catabolism of low-density lipoprotein aggregates

2019 ◽  
Author(s):  
Rajesh K. Singh ◽  
Abigail S. Haka ◽  
Arky Asmal ◽  
Valéria C. Barbosa-Lorenzi ◽  
Inna Grosheva ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Knockout Mice ◽  
Lipid Accumulation ◽  
Foam Cell ◽  
Cell Formation ◽  
Adaptor Protein ◽  
Foam Cell Formation ◽  
Low Density

ABSTRACTObjectiveAggregation and modification of low-density lipoproteins (LDL) promotes their retention and accumulation in the arteries. This is a critical initiating factor during atherosclerosis. Macrophage catabolism of aggregated LDL (agLDL) occurs using a specialized extracellular, hydrolytic compartment, the lysosomal synapse (LS). Compartment formation by local actin polymerization and delivery of lysosomal contents by exocytosis promotes acidification of the compartment and degradation of agLDL. Internalization of metabolites such as cholesterol promotes foam cell formation, a process that drives atherogenesis. Further, there is accumulating evidence for the involvement of TLR4 and its adaptor protein MyD88 in atherosclerosis. Here, we investigated the role of TLR4 in catabolism of agLDL using the LS and foam cell formation.Approach and ResultsUsing bone marrow-derived macrophages (BMMs) from knockout mice, we find that TLR4 and MyD88 regulate compartment formation, lysosome exocytosis, acidification of the compartment and foam cell formation. Using siRNA, pharmacological inhibition and knockout BMMs, we implicate SYK, PI3 kinase and Akt in agLDL catabolism using the LS. Using bone marrow transplantation of LDL receptor knockout mice with TLR4KO bone marrow, we show that deficiency of TLR4 protects macrophages from lipid accumulation during atherosclerosis. Finally, we demonstrate that macrophages in vivo form an extracellular compartment and exocytose lysosome contents similar to that observed in vitro for degradation of agLDL.ConclusionsWe present a mechanism in which interaction of macrophages with agLDL initiates a TLR4 signaling pathway, resulting in formation of the LS, catabolism of agLDL and lipid accumulation in vitro and in vivo.

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.

scholarly journals TLR4 (Toll-Like Receptor 4)-Dependent Signaling Drives Extracellular Catabolism of LDL (Low-Density Lipoprotein) Aggregates

2020 ◽  
Vol 40 (1) ◽  
pp. 86-102 ◽  
Author(s):  
Rajesh K. Singh ◽  
Abigail S. Haka ◽  
Arky Asmal ◽  
Valéria C. Barbosa-Lorenzi ◽  
Inna Grosheva ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Knockout Mice ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Low Density ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

Objective: Aggregation and modification of LDLs (low-density lipoproteins) promote their retention and accumulation in the arteries. This is a critical initiating factor during atherosclerosis. Macrophage catabolism of agLDL (aggregated LDL) occurs using a specialized extracellular, hydrolytic compartment, the lysosomal synapse. Compartment formation by local actin polymerization and delivery of lysosomal contents by exocytosis promotes acidification of the compartment and degradation of agLDL. Internalization of metabolites, such as cholesterol, promotes foam cell formation, a process that drives atherogenesis. Furthermore, there is accumulating evidence for the involvement of TLR4 (Toll-like receptor 4) and its adaptor protein MyD88 (myeloid differentiation primary response 88) in atherosclerosis. Here, we investigated the role of TLR4 in catabolism of agLDL using the lysosomal synapse and foam cell formation. Approach and Results: Using bone marrow–derived macrophages from knockout mice, we find that TLR4 and MyD88 regulate compartment formation, lysosome exocytosis, acidification of the compartment, and foam cell formation. Using siRNA (small interfering RNA), pharmacological inhibition and knockout bone marrow–derived macrophages, we implicate SYK (spleen tyrosine kinase), PI3K (phosphoinositide 3-kinase), and Akt in agLDL catabolism using the lysosomal synapse. Using bone marrow transplantation of LDL receptor knockout mice with TLR4 knockout bone marrow, we show that deficiency of TLR4 protects macrophages from lipid accumulation during atherosclerosis. Finally, we demonstrate that macrophages in vivo form an extracellular compartment and exocytose lysosome contents similar to that observed in vitro for degradation of agLDL. Conclusions: We present a mechanism in which interaction of macrophages with agLDL initiates a TLR4 signaling pathway, resulting in formation of the lysosomal synapse, catabolism of agLDL, and lipid accumulation in vitro and in vivo.

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 35: Elevated MicroRNA-155 Targets HBP1 to Promote the Formation of Macrophage-Derived Foam Cell and This Can Be Effectively Suppressed by YY1/HDACs Complex

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Qing Jing ◽  
Fu-Ju Tian ◽  
Qing Li ◽  
Jun Zou
Keyword(s):  
Promoter Region ◽  
Foam Cell ◽  
Cell Formation ◽  
Pcr Analysis ◽  
Foam Cell Formation ◽  
Ros Production ◽  
Lipid Uptake ◽  
Rt Pcr ◽  
Novel Target

Aims: We aim to investigate the role of microRNAs in the formation of macrophage-derived foam cell. Methods and results: Using quantitative RT-PCR, we found that the level of microRNA-155 (miR-155), a macrophage-associated microRNA, was significantly increased both in plasma of atherosclerotic ApoE-/- mice and in macrophages isolated from this animal model. Indeed, oxLDL effectively induced expression and release of miR-155 in macrophages. We further identified that miR-155 was required to mediate oxLDL-induced lipid uptake and ROS production of macrophages. Importantly, ectopic overexpression and knockdown experiments identified that HMG box-containing protein 1(HBP1) is a novel target of miR-155. Knockdown of HBP1considerably enhanced lipid uptake and ROS production in oxLDL-induced macrophages, and overexpression of HBP1 effectively repressed these effects caused by miR-155 overexpression. Interestingly, bioinformatics analysis identified three YY1 binding sites in promoter region of pri-miR- 155. EMSA and ChIP analyses verified YY1 directly binding to its promoter region. Furthermore, quantitative RT-PCR analysis showed that YY1/HDAC2/4 complex negatively regulated the expression of miR-155 to suppress foam cell formation. Conclusions: In oxLDL-induced macrophages, elevated miR-155 directly targets HBP1 to promote lipid uptake and ROS production, and YY1/HDAC2/4 complex effectively inhibits foam cell formation mediated by miR-155. This study reveals a novel molecular mechanism in the atherosclerosis and suggests miR-155 is a potential therapeutic target.

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