Abstract TP228: Fluorescent Pegylated Nanoparticles are Localized in Macrophage-rich but Relatively Stable Human Carotid Atheromata

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Su-Kyoung Lee ◽  
Hyo-Jin Kim ◽  
Young Jun Choi ◽  
Joo Young Kwon ◽  
Jeong-Yeon Kim ◽  
...  
Keyword(s):  
Foam Cell ◽  
Proteolytic Enzymes ◽  
Fluid Phase ◽  
Foam Cells ◽  
Low Risk ◽  
Foam Cell Formation ◽  
Atherosclerotic Plaques ◽  
Type I ◽  
Atherosclerotic Lesions ◽  
Pegylated Nanoparticles

Background: Foam cell macrophages to produce matrix-disorganizing proteolytic enzymes may render atherosclerotic plaques prone to rupture, which causes thromboembolic stroke. Macrophages within atherosclerotic lesions were reported to take up low density lipoprotein (LDL)-sized nanoparticles by fluid-phase pinocytosis, indicating that fluid-phase pinocytosis of LDL is a mechanism for macrophage foam cell formation in vivo. Objective: To invesigate if fluorescent pegylated nanoparticles that are taken up by macrophages via pinocytosis could visualize vulnerable areas of human atheromata. Methods: Fresh carotid specimens from 36 patients undergoing carotid endarterectomy (after 3T carotid MRI) were tissue-cultured in DMEM (4 mL) with the fluorescent molecular imaging probe in 37°C CO 2 incubator. Before and 4 hours after the incubation, molecular optical imaging was performed using a Cy5.5 near-infrared fluorescent (NIRF) imaging machine with a charge-coupled device camera. The atherosclerotic plaques were classified according to the American Heart Association Report using 35 microsections (5μm thickness) from various pre-determined regions of selected carotid tissues (n=11). Immunohistochemical staining for macrophages (CD68) was performed using the avidin-biotin-peroxidase method. Results: High risk lesions (AHA Type IV ~ VIII) tended to show more frequent plaque regions with strong CD68 immunoreactivity (22 / 27) than did low risk lesion (2 / 8, p = 0.003). Unexpectedly however, low risk lesions (Type I: intial lesion with foam cells; Type II: fatty steak with multiple foam cell layers) tended to show more frequent in plaque regions with both strong CD68 immunoreactivity and high Cy5.5 NIRF signal (11 / 14) than the others (10 / 21, p = 0.07), suggesting that the nanoparticles could be taken up by relatively fresh foam cells in early atherosclerotic lesions rather than end-stage apoptonecrotic macrophages in advanced atheromata. Conclusion: Preliminary analysis of this on-going prospective study shows that fluorescent pegylated nanoparticles may localize macrophage-rich but relatively stable regions of human atheromata.

Abstract 3758: Preventive Effects of Heregulin-Beta1 on Macrophage Foam Cell Formation and Atherosclerosis

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Takuya Watanabe ◽  
Yoshitaka Iso ◽  
Shinji Koba ◽  
Tetsuo Sakai ◽  
Gang Xu ◽  
...  
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Apolipoprotein A1 ◽  
Foam Cell Formation ◽  
Type I ◽  
Macrophage Foam Cell ◽  
Human Macrophages ◽  
Coronary Syndrome ◽  
Atherosclerotic Lesions ◽  
Mild Hypertensive

Human heregulins, neuregulin-1 type I polypeptides known to activate proliferation, differentiation, and survival of glial cells, neurons, and myocytes, were recently found to be expressed in macrophage foam cells within human coronary atherosclerotic lesions. Macrophage foam cell formation, characterized by cholesterol ester (CE) accumulation, is modulated by scavenger receptor class A (SR-A), acyl-CoA:cholesterol acyltransferase-1 (ACAT1), and ATP-binding cassette transporter A1 (ABCA1). The present study clarified the functional roles of heregulins in macrophage foam cell formation and atherosclerosis. Plasma heregulin-beta1 levels were significantly decreased in 31 patients with acute coronary syndrome (ACS) and 33 patients with stable angina pectoris as compared with 34 mild hypertensive patients and 40 healthy volunteers (1.3+/−0.3, 2.0+/−0.4 versus 7.6+/−1.4, 8.2+/−1.2 ng/mL; at least P < 0.01). Immunoreactive heregulins and these receptor c-erbB3 were detectable within human coronary atherothrombosis obtained from ACS patients. In primary cultured human monocyte-macrophages, the expression of endogenous heregulins, heregulin-beta1, and c-erbB3 increased during monocytic differentiation into macrophages. In human macrophages differentiated by 7-day culture, exogenous heregulin-beta1, but not heregulin-alpha, significantly reduced acetylated low-density lipoprotein (acLDL)-induced CE accumulation by reducing SR-A and ACAT1 expression and by increasing ABCA1 expression at both mRNA and protein levels. Heregulin-beta1 significantly decreased endocytic uptake of [ 125 I]acLDL and increased cholesterol efflux by apolipoprotein A1 from human macrophages. Chronic infusion of heregulin-beta1 by osmotic mini-pumps into apolipoprotein E-deficient mice significantly suppressed the progression of macrophage-driven atherosclerotic lesions by 64%. Our study provides the first evidence that heregulin-beta1 may participate in anti-atherogenesis by suppressing macrophage foam cell formation via SR-A and ACAT1 down-regulation and ABCA1 up-regulation.

Abstract 633: Macrophage SR-BI Suppresses Atherosclerosis by Modulation of Autophagy via VPS34/Belclin-1 Pathway

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Huan Tao ◽  
Patricia G Yancey ◽  
John L Blakemore ◽  
Youmin Zhang ◽  
Lei Ding ◽  
...  
Keyword(s):  
Foam Cell ◽  
Oxidized Ldl ◽  
Cell Formation ◽  
Atherosclerotic Lesion ◽  
Beclin 1 ◽  
Foam Cell Formation ◽  
Aortic Tissue ◽  
Type I ◽  
Macrophage Foam Cell ◽  
Atherosclerotic Lesions

Background: Autophagy modulates vascular cell lipid metabolism, lipid droplet turnover, foam cell formation, cell survival and death, and inflammation. Scavenger receptor class B type I (SR-BI) deficiency causes impaired lysosome function in macrophages and erythrocytes. Methods and Results: Bone marrow transplantation studies were performed in ApoE and LDLR deficient mice to examine the effects of hematopoietic SR-BI deletion on atherosclerotic lesion autophagy. In addition, in vitro studies compared WT versus SR-BI -/- macrophages. Under conditions of cholesterol induced stress, the mRNA and protein levels of critical autophagy players including ATG5, ATG6/Belcin-1, ATG7 and LC3II were decreased by 37.8% to 84.6% (P<0.05 to 0.01) in SR-B1 -/- macrophages and atherosclerotic aortic tissue compared to controls. Electron microscopic analysis showed that SR-BI -/- versus WT macrophages had 80% fewer (P<0.05) autophagsomes in response to cholesterol enrichment. Macrophage SR-BI deficiency led to 1.8-fold (P<0.05) more lipid deposition and 2.5-fold more (P<0.01) apoptosis in response to oxidized LDL. Furthermore, hematopoietic SR-BI deletion caused 2.3 fold (P<0.05) more cell death in aortic atherosclerotic lesions compared to the WT control. Pharmacologic activation of autophagy did not reduce the levels of lipid droplets or cell apoptosis in SR-BI null macrophages vs WT control. WT peritoneal macrophages were used to examine SR-BI subcellular distribution and its interaction with VPS34/Beclin-1. In response to induction of autophagy, macrophage SR-BI was expressed in lysosomes and co-localized with LC3-II. Furthermore, we found that SR-BI directly interacted with the VPS34/Beclin-1 complex. Conclusions: SR-BI deficiency leads to defective autophagy and accelerates macrophage foam cell formation and apoptosis in experimental mouse atherosclerotic lesions. Macrophage SR-BI regulates expression of critical autophagy players and directly modulates autophagy via the VPS34/Beclin-1 pathway, identifying novel targets for the treatment of 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.

Inhibitory effects of vasostatin-1 against atherogenesis

2018 ◽  
Vol 132 (23) ◽  
pp. 2493-2507 ◽  
Author(s):  
Yuki Sato ◽  
Rena Watanabe ◽  
Nozomi Uchiyama ◽  
Nana Ozawa ◽  
Yui Takahashi ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Inflammatory Responses ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Inhibitory Effects ◽  
Macrophage Foam Cell ◽  
Down Regulation ◽  
Atherosclerotic Lesions

Vasostatin-1, a chromogranin A (CgA)-derived peptide (76 amino acids), is known to suppress vasoconstriction and angiogenesis. A recent study has shown that vasostatin-1 suppresses the adhesion of human U937 monocytes to human endothelial cells (HECs) via adhesion molecule down-regulation. The present study evaluated the expression of vasostatin-1 in human atherosclerotic lesions and its effects on inflammatory responses in HECs and human THP-1 monocyte-derived macrophages, macrophage foam cell formation, migration and proliferation of human aortic smooth muscle cells (HASMCs) and extracellular matrix (ECM) production by HASMCs, and atherogenesis in apolipoprotein E-deficient (ApoE−/−) mice. Vasostatin-1 was expressed around Monckeberg’s medial calcific sclerosis in human radial arteries. Vasostatin-1 suppressed lipopolysaccharide (LPS)-induced up-regulation of monocyte chemotactic protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in HECs. Vasostatin-1 suppressed inflammatory M1 phenotype and LPS-induced interleukin-6 (IL-6) secretion via nuclear factor-κB (NF-κB) down-regulation in macrophages. Vasostatin-1 suppressed oxidized low-density lipoprotein (oxLDL)-induced foam cell formation associated with acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) and CD36 down-regulation and ATP-binding cassette transporter A1 (ABCA1) up-regulation in macrophages. In HASMCs, vasostatin-1 suppressed angiotensin II (AngII)-induced migration and collagen-3 and fibronectin expression via decreasing ERK1/2 and p38 phosphorylation, but increased elastin expression and matrix metalloproteinase (MMP)-2 and MMP-9 activities via increasing Akt and JNK phosphorylation. Vasostatin-1 did not affect the proliferation and apoptosis in HASMCs. Four-week infusion of vasostatin-1 suppressed the development of aortic atherosclerotic lesions with reductions in intra-plaque inflammation, macrophage infiltration, and SMC content, and plasma glucose level in ApoE−/− mice. These results indicate the inhibitory effects of vasostatin-1 against atherogenesis. The present study provided the first evidence that vasostatin-1 may serve as a novel therapeutic target for atherosclerosis.

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 Cholesterol Acceptors Regulate the Lipidome of Macrophage Foam Cells

2019 ◽  
Vol 20 (15) ◽  
pp. 3784 ◽  
Author(s):  
Antoni Paul ◽  
Todd A. Lydic ◽  
Ryan Hogan ◽  
Young-Hwa Goo
Keyword(s):  
High Density Lipoprotein ◽  
Free Cholesterol ◽  
Foam Cell ◽  
Density Lipoprotein ◽  
Foam Cells ◽  
Atherosclerotic Plaques ◽  
Plaque Instability ◽  
Apolipoprotein A ◽  
Lipid Species ◽  
Macrophage Foam Cells

Arterial foam cells are central players of atherogenesis. Cholesterol acceptors, apolipoprotein A-I (apoA-I) and high-density lipoprotein (HDL), take up cholesterol and phospholipids effluxed from foam cells into the circulation. Due to the high abundance of cholesterol in foam cells, most previous studies focused on apoA-I/HDL-mediated free cholesterol (FC) transport. However, recent lipidomics of human atherosclerotic plaques also identified that oxidized sterols (oxysterols) and non-sterol lipid species accumulate as atherogenesis progresses. While it is known that these lipids regulate expression of pro-inflammatory genes linked to plaque instability, how cholesterol acceptors impact the foam cell lipidome, particularly oxysterols and non-sterol lipids, remains unexplored. Using lipidomics analyses, we found cholesterol acceptors remodel foam cell lipidomes. Lipid subclass analyses revealed various oxysterols, sphingomyelins, and ceramides, species uniquely enriched in human plaques were significantly reduced by cholesterol acceptors, especially by apoA-I. These results indicate that the function of lipid-poor apoA-I is not limited to the efflux of cholesterol and phospholipids but suggest that apoA-I serves as a major regulator of the foam cell lipidome and might play an important role in reducing multiple lipid species involved in the pathogenesis of atherosclerosis.

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.

NUMERICAL MODELING OF ATHEROSCLEROSIS LESION EVOLUTION IN TIME I. INITIAL STAGE OF THE DISEASE

2016 ◽  
Vol 16 (05) ◽  
pp. 1650068
Author(s):  
SAFOORA KARIMI ◽  
MITRA DADVAR ◽  
BAHRAM DABIR
Keyword(s):  
Inflammatory Responses ◽  
Foam Cell ◽  
Cell Formation ◽  
Ldl Oxidation ◽  
Foam Cell Formation ◽  
Type I ◽  
Specific Patient ◽  
Disease Evolution ◽  
Endothelium Dysfunction ◽  
Initial Stage

Atherosclerosis is one of the main causes of death in the developed world. The disease, which is an inflammatory disease, has been the focus of many studies. A few studies attempted to model atherosclerosis lesion development mathematically while no attention has been paid to the multistage nature of the disease. The present study provides a mathematical model for atherosclerosis evolution by focusing on the inflammatory responses of the initial stage of the disease. In the model, the inflammatory response in type I lesion, which includes endothelium dysfunction, LDL oxidation, monocytes entry, foam cell formation and intima property changes, are coupled with the transport equations of blood and LDL in lumen and arterial wall. The innovation of the model is determination of the duration of the initial stage of lesion propagation for a specific patient while the presence of leaky junction in endothelial layer and LDL oxidation in the intima layer are considered. The greatest advantage of the study in comparison with previous studies is to provide a model for the initiating stage of the atherosclerosis development so that a more precise result of the disease evolution is obtained.

The Biological Effects of Interleukin-17A on Adhesion Molecules Expression and Foam Cell Formation in Atherosclerotic Lesions

2019 ◽  
Vol 39 (11) ◽  
pp. 694-702 ◽  
Author(s):  
Shohei Shiotsugu ◽  
Toshinori Okinaga ◽  
Manabu Habu ◽  
Daigo Yoshiga ◽  
Izumi Yoshioka ◽  
...  
Keyword(s):  
Adhesion Molecules ◽  
Foam Cell ◽  
Biological Effects ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Atherosclerotic Lesions ◽  
Interleukin 17A

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.

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