Abstract 254: A Novel Role of Endothelial and Macrophage Epsins in Atherosclerosis

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Hong Chen
Keyword(s):  
Atherosclerotic Plaque ◽  
Foam Cell ◽  
Cell Formation ◽  
Atherosclerotic Lesion ◽  
Mapk Signaling ◽  
Leukocyte Recruitment ◽  
Foam Cell Formation ◽  
Tlr Signaling ◽  
M1 Macrophage

Background: Epsins are a family of ubiquitin-binding endocytic clathrin adaptors. We recently published that endothelial epsins function as critical regulators of tumor angiogenesis by controlling VEGF signaling (JCI, 2012; ATVB, 2013). Our goal is to define the novel role of epsins in endothelial cells (EC) and macrophages in regulating atherogenesis. Methods and Results: We engineered mice with specific deletion of epsins in EC (EC-DKO) or myeloid cells (MΦ-DKO). Strikingly, either EC-DKO or MΦ-DKO mice on ApoE-/- background fed western diet significantly reduced atherosclerotic lesion formation and foam cell accumulation. FACS analysis revealed that epsin deficiency greatly reduced TNFα and LPS-induced adhesion molecule expression (ICAM-1, VCAM-1, P- and E-selectins, CCR2 and MCP-1) in aortic EC and leukocyte recruitment in aorta. Mechanistically, EC epsins promote TNFR/TLR signaling and NF-κB and MAPK activation by recruiting NEMO, an essential NF-κB activator. In macrophages, epsin deficiency did not alter LDL scavenger receptors, CD36, Lox1 or SRB1, or reverse cholesterol transport proteins, ABCA1 or ABCG1, but did significantly reduce Lucifer Yellow pinocytosis, indicating a major defect in lipid uptake. Oil Red O staining of isolated ApoE-/-/MΦ-DKO macrophages showed little lipid accumulation, suggesting a mechanism in which epsin deficiency impairs foam cell formation. Epsin deficiency also significantly suppressed the pro-inflammatory M1 macrophage phenotype found in plaques thus suggesting an important pro-inflammatory role for epsins in macrophages. Loss of macrophage epsins significantly inhibited TNFα-stimulated activation of NF-κB and MAPK signaling pathways. We also observed a synthetic peptide comprising the epsin ubiquitin-interacting motif (UIM) and lesion homing sequence potently disrupted association of epsins with TNFR/TLR signaling complex in vitro, and inhibited atherosclerotic plaque in vivo. Conclusions: We demonstrate epsins promote atherogenesis by potentiating endothelium activation, leukocyte recruitment, foam cell formation and maintaining pro-inflammatory macrophages within the atherosclerotic plaque, thus suggesting epsins as a novel therapeutic target to combat atherogenesis.

Dynamic Role of Macrophage Sub Types for Development of Atherosclerosis and Potential Use of Herbal Immunomodulators as Imminent Therapeutic Strategy

2020 ◽  
Vol 18 ◽  
Author(s):  
Parimalanandhini Duraisamy ◽  
Sangeetha Ravi ◽  
Mahalakshmi Krishnan ◽  
Catherene M. Livya ◽  
Beulaja Manikandan ◽  
...  
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Atherosclerotic Lesion ◽  
Foam Cell Formation ◽  
Atherosclerosis Progression ◽  
Proinflammatory Mediators ◽  
M1 Macrophage ◽  
Tnf Α ◽  
Inflammatory Site

: Atherosclerosis, a major contributor to cardiovascular disease is a global alarm causing mortality worldwide. Being a progressive disease in the arteries, it mainly causes recruitment of monocytes to the inflammatory sites and subside pathological conditions. Monocyte-derived macrophage mainly acts in foam cell formation by engorging the LDL molecules, oxidizes it into Ox-LDL and leads to plaque deposit development. Macrophages in general differentiate, proliferate and undergo apoptosis at the inflammatory site. Frequently two subtypes of macrophages M1 and M2 has to act crucially in balancing the micro-environmental conditions of endothelial cells in arteries. The productions of proinflammatory mediators like IL-1, IL-6, TNF-α by M1 macrophage has atherogenic properties majorly produced during the early progression of atherosclerotic plaques. To counteract cytokine productions and M1-M2 balance, secondary metabolites (phytochemicals) from plants act as a therapeutic agent in alleviating atherosclerosis progression. This review summarizes the fundamental role of the macrophage in atherosclerotic lesion formation along with its plasticity characteristic as well as recent therapeutic strategies using herbal components and anti-inflammatory cytokines as potential immunomodulators.

Differentiation factors and cytokines in the atherosclerotic plaque micro-environment as a trigger for macrophage polarisation

2011 ◽  
Vol 106 (11) ◽  
pp. 763-771 ◽  
Author(s):  
Ine Wolfs ◽  
Marjo Donners ◽  
Menno de Winther
Keyword(s):  
Inflammatory Cell ◽  
Foam Cell ◽  
Cell Formation ◽  
Atherosclerotic Lesion ◽  
Foam Cell Formation ◽  
M1 Macrophages ◽  
Macrophage Polarisation ◽  
Atherosclerotic Lesions ◽  
Differentiation Factors

SummaryThe phenotype of macrophages in atherosclerotic lesions can vary dramatically, from a large lipid laden foam cell to a small inflammatory cell. Classically, the concept of macrophage heterogeneity discriminates between two extremes called either pro-inflammatory M1 macrophages or anti-inflammatory M2 macrophages. Polarisation of plaque macrophages is predominantly determined by the local micro-environment present in the atherosclerotic lesion and is rather more complex than typically described by the M1/M2 paradigm. In this review we will discuss the role of various polarising factors in regulating the phenotypical state of plaque macrophages. We will focus on two main levels of phenotype regulation, one determined by differentiation factors produced in the lesion and the other determined by T-cell-derived polarising cytokines. With foam cell formation being a key characteristic of macrophages during atherosclerosis initiation and progression, these polarisation factors will also be linked to lipid handling of macrophages.

Abstract 239: Deficiency of Macrophage Epsins Impedes Atherosclerosis by Inhibiting LRP-1 Internalization and Degradation

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Megan L Brophy ◽  
Ashiqur Rahman ◽  
Yunzhou Dong ◽  
Hao Wu ◽  
Kandice L Tessneer ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Foam Cell ◽  
Cell Formation ◽  
Atherosclerotic Lesion ◽  
Gene Profiling ◽  
Foam Cell Formation ◽  
Macrophage Phenotype ◽  
M1 Macrophage ◽  
Anti Inflammatory ◽  
Inflammatory Macrophage

Background: Atherosclerosis is caused by the chronic activation of the vascular endothelium and immune and inflammatory cell infiltration of the vascular wall, leading to enhanced inflammation and lipid accumulation. Understanding the molecular mechanisms underlying this disease is critical for the development of new therapies. Epsins are a family of ubiquitin-binding endocytic adaptors. However, their role in vascular inflammation is poorly understood. Our goal is to define the novel role of epsins in regulating atherogenesis. Methods and Results: We engineered mice with specific deletion of epsins in myeloid cells (MΦ-DKO). Strikingly, MΦ-DKO mice on an ApoE-/- background fed western diet exhibited reduced atherosclerotic lesion and foam cell accumulation, and diminished recruitment of immune or inflammatory cells to aortas by FACS analysis. In primary macrophages, epsin deficiency impaired foam cell formation by Oil Red O staining, and suppressed the pro-inflammatory M1 macrophage phenotype but increased the anti-inflammatory macrophage phenotype by gene profiling. Epsin deficiency did not alter levels of LDL scavenger receptors, or reverse cholesterol transport proteins, but did increase total and surface levels of LRP-1, a protein with anti-inflammatory and anti-atherosclerotic properties. Mechanistically, Epsin interacts with LRP-1 via epsin’s UIM domain. LPS treatment increased LRP-1 ubiquitination and subsequent binding to epsin, suggesting that epsin promotes the ubiquitin-dependent internalization and degradation of LRP-1. Accordingly, macrophages isolated from MΦ-DKO mice on LRP-1 heterozygous background restored the pro-inflammatory phenotype. Conclusions: Epsins promote atherogenesis by facilitating pro-inflammatory macrophage recruitment and potentiating foam cell formation by downregulating LRP-1 implicating that targeting the epsin-LRP-1 interaction may serve as a novel therapeutic strategy to treat atheromas.

Abstract 474: Atherosclerotic Macrophages Develop a Progressive Lysosomal Dysfunction that can be Rescued by Induction of a Lysosomal Biogenesis Program

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Roy Emanuel ◽  
Ismail Sergin ◽  
Babak Razani
Keyword(s):  
Atherosclerotic Plaque ◽  
Foam Cell ◽  
Oxidized Ldl ◽  
Membrane Integrity ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Lysosomal Function ◽  
Lysosomal Dysfunction ◽  
Lipid Species

Recent reports of the proatherogenic phenotype of mice with a macrophage-specific autophagy deficiency has renewed interest in the role of the autophagy-lysosomal system in atherosclerosis. Lysosomes have the unique role of serving to process both exogenous material including the excess of atherogenic lipids and endogenous cargo including dysfunctional proteins and organelles. Surprisingly, little is known about the effect of an atherogenic environment on macrophage lysosomes. To address this, we utilize a variety of complementary techniques to show that oxidized LDL and cholesterol crystals, two of the commonly encountered lipid species in the atherosclerotic plaque, create a profound lysosomal dysfunction in cultured peritoneal macrophages. Disruptions in lysosomal pH, enzyme activity, proteolytic capacity, membrane integrity, and morphology are readily seen when cells are incubated with such lipids. Using flow cytometry to isolate resident tissue macrophages, we show that atherosclerotic plaque macrophages show features of dysfunctional lysosomes, a process that appears to be progressive with advanced plaque formation. These observations lead us to investigate whether stimulation of lysosomal function can ameliorate some of these effects. TFEB is the only known transcription factor that acts as a master regulator of lysosomal biogenesis, although its role in macrophages has not been studied. We show that overexpression of TFEB in cultured macrophages initiates a robust prodegradative response including induction of lysosomal genes and the generation of nascent lysosomes. Interestingly, this response can rescue several deleterious effects seen with atherogenic lipid loading including reductions in the secretion of the proinflammatory cytokine IL-1β and reductions in foam cell formation. Taken together, these data demonstrate that lysosomal function is markedly impaired in atherosclerosis and suggest that induction of a lysosomal biogenesis program can have anti-atherogenic effects.

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 3691: Deletion of Suppressor Of Cytokine Signaling-1 in a Murine Model of Atherosclerosis Results in a Lethal Systemic Inflammation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Christina Grothusen ◽  
Harald Schuett ◽  
Stefan Lumpe ◽  
Andre Bleich ◽  
Silke Glage ◽  
...  
Keyword(s):  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
The Impact

Introduction: Atherosclerosis is a chronic inflammatory disease of the cardiovascular system which may result in myocardial infarction and sudden cardiac death. While the role of pro-inflammatory signaling pathways in atherogenesis has been well characterized, the impact of their negative regulators, e.g. suppressor of cytokine signaling (SOCS)-1 remains to be elucidated. Deficiency of SOCS-1 leads to death 3 weeks post-partum due to an overwhelming inflammation caused by an uncontrolled signalling of interferon-gamma (IFNγ). This phenotype can be rescued by generating recombination activating gene (rag)-2, SOCS-1 double knock out (KO) mice lacking mature lymphocytes, the major source of IFNγ. Since the role of SOCS-1 during atherogenesis is unknown, we investigated the impact of a systemic SOCS-1 deficiency in the low-density lipoprotein receptor (ldlr) KO model of atherosclerosis. Material and Methods: socs-1 −/− /rag-2 −/− deficient mice were crossed with ldlr-KO animals. Mice were kept under sterile conditions on a normal chow diet. For in-vitro analyses, murine socs-1 −/− macrophages were stimulated with native low density lipoprotein (nLDL) or oxidized (ox)LDL. SOCS-1 expression was determined by quantitative PCR and western blot. Foam cell formation was determined by Oil red O staining. Results: socs-1 −/− /rag-2 −/− /ldlr −/− mice were born according to mendelian law. Tripel-KO mice showed a reduced weight and size, were more sensitive to bacterial infections and died within 120 days (N=17). Histological analyses revealed a systemic, necrotic, inflammation in Tripel-KO mice. All other genotypes developed no phenotype. In-vitro observations revealed that SOCS-1 mRNA and protein is upregulated in response to stimulation with oxLDL but not with nLDL. Foam cell formation of socs-1 −/− macrophages was increased compared to controls. Conclusion: SOCS-1 seemingly controls critical steps of atherogenesis by modulating foam cell formation in response to stimulation with oxLDL. SOCS-1 deficiency in the ldlr-KO mouse leads to a lethal inflammation. These observations suggest a critical role for SOCS-1 in the regulation of early inflammatory responses in atherogenesis.

scholarly journals Gasdermin D mediates inflammation-induced defects in reverse cholesterol transport and promotes atherosclerosis.

2021 ◽  
Author(s):  
Emmanuel Opoku ◽  
Cynthia Alicia Traughber ◽  
David Zhang ◽  
Amanda J Iacano ◽  
Mariam Khan ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Reverse Cholesterol Transport ◽  
Foam Cell ◽  
Atherosclerotic Lesion ◽  
Foam Cell Formation ◽  
Cholesterol Transport ◽  
Inflammasome Activation ◽  
Lesion Area ◽  
Direct Role

Nlrp3 inflammasome is activated in advanced human atherosclerotic plaques. Gasdermin D (GsdmD) serves as a final executor of Nlrp3 inflammasome activity, by generating membrane pores for the release of mature Interleukin-1beta (IL-b). Inflammation dampens reverse cholesterol transport (RCT) and promotes atherogenesis, while anti-IL-1b; antibodies were shown to reduce cardiovascular disease in humans. Though Nlrp3/IL-1b; nexus is an emerging atherogenic pathway, the direct role of GsdmD in atherosclerosis is not yet clear. Here, we used in-vivo Nlrp3 inflammasome activation to show that the GsdmD-/- mice release ~80% less IL-1b; vs WT mice. The GsdmD-/- macrophages were more resistant to Nlrp3 inflammasome mediated reduction in cholesterol efflux, showing ~26% decrease vs. ~60% reduction in WT macrophages. GsdmD expression in macrophages exacerbated foam cell formation in an IL-1b; dependent fashion. The GsdmD-/- mice were resistance to Nlrp3 inflammasome mediated defect in RCT, with ~32% reduction in plasma RCT vs. ~ 57% reduction in WT mice, ~ 17% reduction in RCT to liver vs. 42% in WT mice, and ~ 37% decrease in RCT to feces vs. ~ 61% in WT mice. The LDLr anti-sense oligonucleotides (ASO) induced hyperlipidemic mouse model showed role of GsdmD in promoting atherosclerosis. The GsdmD-/- mice exhibit ~42% decreased atherosclerotic lesion area in females and ~33% decreased lesion area in males vs. WT mice. The atherosclerotic plaque-bearing WT mice showed the presence of cleaved N-terminal fragment of GsdmD, indicating cleavage of GsdmD during atherosclerosis. Our data show that GsdmD mediates inflammation-induced defect in RCT and promotes atherosclerosis.

Abstract 249: Increased Vascular CCRL2 Expression by Disturbed Blood Flow Promotes Atherosclerotic Plaque Formation in ApoE Deficient Mice

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Shuhong Hu ◽  
Li Zhu
Keyword(s):  
Blood Flow ◽  
Atherosclerotic Plaque ◽  
Inflammatory Responses ◽  
Foam Cell ◽  
Cell Formation ◽  
Vascular Wall ◽  
Chronic Inflammatory Disease ◽  
Plaque Formation ◽  
Foam Cell Formation ◽  
Cell Trafficking

Atherosclerosis is a chronic inflammatory disease of the arterial wall elicited by accumulation of LDL and leucocytes in the subendothelium at predilection sites with disturbed laminar flow. Chemokines and their receptors appear to act as critical players in atherosclerosis as they not only direct atherogenic recruitment of leucocytes but also exert cell hemostatic functions by chemokine ligand-receptor axes and their specific or combined contributions. Atypical chemokine (C-C motif) receptor-like 2 (CCRL2) cooperates with its ligand chemerin and leukocyte-expressed chemerin receptor chemokine-like receptor 1 (CMKLR1) to regulate cell trafficking and inflammatory responses,but its role in atherosclerosis is not clear. To investigate whether CCRL2 contributes to the pathomechanism of atherogenesis, we generated CCRL2 -/- mice in hyperlipidemic atherosclerosis-prone ApoE -/- background and found that the atherosclerotic plaque area of the total aorta was significantly reduced compared with CCRL2 +/+ ApoE -/- mice on a high fat diet. The protective effect of CCRL2 deficiency was anatomically isolated primarily to the site of disturbed blood flow (D-flow) in the aortic arch but not in the descending aorta. Endothelial CCRL2 was upregulated in response to D-flow and either CCRL2 or CMKLR1 deletion reduced plaque formation. Further studies showed that CCRL2 co-localized with CMKLR1 and chemerin within the atherosclerotic aorta root. CCRL2 deficiency led to significantly less lipid deposition in aortic root, reduced CMKLR1 + leukocyte rolling on lesional vascular endothelium, diminished macrophage accumulation and foam cell formation, and polarized macrophage to an M2-like phenotype. These results demonstrate that D-flow induction of vascular CCRL2 is required for optimal formation of atherosclerotic plaques via coordinating the accumulation of CMKLR1 + monocytes/macrophages within the vascular wall, and thus identifies CCRL2 as a novel drug target to prevent or treat atherosclerosis. This work was supported by Natural Science Foundation of China (grant 81370373 to L.Z. and 31300781 to C.T.) Key Words: atherosclerosis, CCRL2, chemerin, macrophage

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.

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