Abstract 113: Mast Cell Plays Pivotal Role in Nicotine-Induced Atherosclerotic Plaque Progress and Instability

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Han Chen ◽  
Chen Wang ◽  
Yinchuan Xu ◽  
Xinyang Hu ◽  
Jian-an Wang
Keyword(s):  
Mast Cell ◽  
Smooth Muscle ◽  
High Fat Diet ◽  
Foam Cell ◽  
Cell Formation ◽  
Mast Cell Degranulation ◽  
Foam Cell Formation ◽  
Macrophage Migration ◽  
High Fat ◽  
Plaque Instability

Objectives: Nicotine has been identified to promote atherosclerosis. But the mechanism of nicotine induced atherogenesis has not been well elucidated. This study focus on the role of mast cell in nicotine induced atherogenesis and plaque instability. Methods: Peritoneal administration of 100mM disodium cromoglicate (DSCG) was introduced to inhibit mast cell degranulation. 45 ApoE deficient mice were divided into 3 groups: high-fat diet, high-fat diet + nicotine, and high-fat diet + nicotine + DSCG. After 12 weeks of treatments, atherosclerotic lesion size of the aortas were quantified. Toluidine blue and tryptase staining identified mast cell count and activation at the lesion. Immuno-staining were used to evaluate the inflammatory filtration, smooth muscle cell proliferation and collagen content in the lesion. In vitro , bone marrow-derived mast cells (BMMCs) were harvested and treated with PBS as a negative control, compound 48/80 as a positive control,100μg/ml nicotine, nicotine with 100mM DSCG pretreatment and nicotine with 10μg/ml mecamylamine pretreatment. At 0.5hr,1hr and 2hrs, supernatants were harvested to analyze the mast cell degranulation. Futhermore, conditioned medium were also used to induce the macrophage migration and foam cell formation. Results: Nicotine increases plaque size, and macrophage infiltration, decreases smooth muscle collagen content along with the increases in mast cells count and activation ratio at the lesion, which could be inhibited by DSCG.Nicotine induced mast cell degranulation at 2 hours comparing to PBS (43.60% vs 2.3%) , which could be inhibited by mast cell stablizer DSCG (23.7%) and nAChR blocker mecamylamine (20.35%). Macrophage migration ability in the compound 48/80 and nicotine conditional medium group were significantly higher comparing to PBS, DSCG and mecamylamine group. Foam cell formation ratio in the compound 48/80 and nicotine conditional group were significantly higher comparing to PBS, DSCG and mecamylamine group. Conclusions: Nicotine induces mast cell degranulation through nAChR and then increases macrophages function, which leads to plaque instability. Administration of mast cell stabilizer showed potential of preventing nicotine induced atherogenesis.

scholarly journals 12-Hydroxyeicosapentaenoic acid inhibits foam cell formation and ameliorates high-fat diet-induced pathology of atherosclerosis in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Takahiro Nagatake ◽  
Yuki Shibata ◽  
Sakiko Morimoto ◽  
Eri Node ◽  
Kento Sawane ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Foam Cell ◽  
Linseed Oil ◽  
Cell Formation ◽  
Chronic Inflammatory Disease ◽  
Foam Cell Formation ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
High Fat ◽  
The Impact

AbstractAtherosclerosis is a chronic inflammatory disease associated with macrophage aggregate and transformation into foam cells. In this study, we sought to investigate the impact of dietary intake of ω3 fatty acid on the development of atherosclerosis, and demonstrate the mechanism of action by identifying anti-inflammatory lipid metabolite. Mice were exposed to a high-fat diet (HFD) supplemented with either conventional soybean oil or α-linolenic acid-rich linseed oil. We found that as mice became obese they also showed increased pulsatility and resistive indexes in the common carotid artery. In sharp contrast, the addition of linseed oil to the HFD improved pulsatility and resistive indexes without affecting weight gain. Histological analysis revealed that dietary linseed oil inhibited foam cell formation in the aortic valve. Lipidomic analysis demonstrated a particularly marked increase in the eicosapentaenoic acid-derived metabolite 12-hydroxyeicosapentaenoic acid (12-HEPE) in the serum from mice fed with linseed oil. When we gave 12-HEPE to mice with HFD, the pulsatility and resistive indexes was improved. Indeed, 12-HEPE inhibited the foamy transformation of macrophages in a peroxisome proliferator-activated receptor (PPAR)γ-dependent manner. These results demonstrate that the 12-HEPE-PPARγ axis ameliorates the pathogenesis of atherosclerosis by inhibiting foam cell formation.

Role of Ox-LDL and LOX-1 in Atherogenesis

2019 ◽  
Vol 26 (9) ◽  
pp. 1693-1700 ◽  
Author(s):  
Ajoe John Kattoor ◽  
Sri Harsha Kanuri ◽  
Jawahar L. Mehta
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Foam Cell ◽  
Leukocyte Adhesion ◽  
Oxidized Ldl ◽  
Cell Formation ◽  
Muscle Cells ◽  
Foam Cell Formation ◽  
Plaque Instability

Oxidized LDL (ox-LDL) plays a central role in atherosclerosis by acting on multiple cells such as endothelial cells, macrophages, platelets, fibroblasts and smooth muscle cells through LOX-1. LOX-1 is a 50 kDa transmembrane glycoprotein that serves as receptor for ox-LDL, modified lipoproteins, activated platelets and advance glycation end-products. Ox- LDL through LOX-1, in endothelial cells, causes increase in leukocyte adhesion molecules, activates pathways of apoptosis, increases reactive oxygen species and cause endothelial dysfunction. In vascular smooth muscle cells and fibroblasts, they stimulate proliferation, migration and collagen synthesis. LOX-1 expressed on macrophages inhibit macrophage migration and stimulate foam cell formation. They also stimulate generation of metalloproteinases and contribute to plaque instability and thrombosis. Drugs that modulate LOX-1 are desirable targets against atherosclerosis. Many naturally occurring compounds have been shown to modulate LOX-1 expression and atherosclerosis. Currently, novel drug design techniques are used to identify molecules that can bind to LOX-1 and inhibit its activation by ox-LDL. In addition, techniques using RNA interference and monoclonal antibody against LOX-1 are currently being investigated for clinical use.

Abstract 450: Modification of HDL by Reactive Aldehydes Impairs HDL's Athero-protective Functions

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Rebecca L Holme ◽  
Alexandra C Chadwick ◽  
Sarah C Proudfoot ◽  
Yiliang Chen ◽  
Devi Prasadh Ramakrishnan ◽  
...  
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Oxidative Modification ◽  
High Density Lipoproteins ◽  
Foam Cell Formation ◽  
Macrophage Migration ◽  
Mrna Levels ◽  
Protective Effects ◽  
Impaired Ability ◽  
Reactive Aldehydes

High density lipoproteins (HDL) are athero-protective particles that promote the removal of excess cholesterol from lipid-loaded macrophages and stimulate their migration in order to protect against foam cell formation, a precursor to atherosclerotic plaque build-up. Recently, studies have shown that oxidative modification of HDL prevents HDL from protecting against atherosclerosis; however, the exact mechanisms by which this occurs are not well defined. We hypothesize that oxidative modification of HDL by reactive aldehydes such as acrolein (a major component of cigarette smoke) and 4-hydroxynonenal (HNE; a product of lipid peroxidation) impairs HDL’s athero-protective effects in macrophages. We tested our hypothesis using three different assays. First, we determined that modified forms of HDL upregulate mRNA levels of pro-atherogenic scavenger receptors such as cluster of differentiation 36 (CD36), a known oxidized LDL receptor. Incubation of macrophages with native HDL did not exert similar effects. Second, we tested the ability of oxidized HDL to prevent foam cell formation. Peritoneal macrophages isolated from WT C57Bl/J mice were cholesterol-loaded and incubated with native HDL, acrolein-modified HDL (acro-HDL), or HNE-modified HDL (HNE-HDL). Oil Red-O staining demonstrated that 24% of macrophages had foam cell formation upon incubation with native HDL, whereas 61% and 49% foam cell formation was observed for acro- and HNE-HDL, respectively. Preliminary data suggests this may be CD36-dependent. Finally, using a Boyden chamber assay, we demonstrated that both acro- and HNE-HDL, but not native HDL, had an impaired ability to promote macrophage migration (43% and 72% of HDL cell migration levels, respectively). We determined that the inability of acro- and/or HNE-HDL to stimulate macrophage migration may be due to an impaired ability of these modified lipoproteins to activate the PI3K pathway, as shown by decreased levels of phosphorylated protein kinase B (Akt). In conclusion, we have identified three independent mechanisms by which modification of HDL with acrolein or HNE impairs HDL’s cardio-protective effects and, instead, generates a particle that promotes pathways that lead to atherosclerosis.

Abstract 451: Bone Marrow-derived Matricellular Protein CCN3 is Protective Against Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Chao Zhang ◽  
Xingjian Hu ◽  
Hong Shi ◽  
Wenconghui Wu ◽  
Yulan Qing ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Fat Diet ◽  
Immune Cell ◽  
Foam Cell ◽  
Reactive Oxygen Species Generation ◽  
Developed Countries ◽  
Foam Cell Formation ◽  
Matricellular Protein ◽  
High Fat ◽  
Double Knockout

Background: Atherosclerosis and its complications (myocardial infarction, stroke, peripheral vascular disease) are the major cause of morbidity and mortality in developed countries. Despite considerable efforts, the underlying pathomechanisms remain incompletely understood. In this study, we examined the role of a matricellular protein termed CCN3 in the pathogenesis of atherosclerosis. Methods and Results: To investigate whether CCN3 deficiency affects the development of atherosclerosis, control (ApoE-/-) and CCN3/ApoE double knockout mice were subjected to high fat diet feeding. In response to 16-week high fat diet feeding, the aortas of CCN3/ApoE double knockout (DKO) mice demonstrated exquisite susceptibility to atherosclerosis formation as evidenced by significantly increased size of aortic lipid-rich plaques in aortic roots, arch, thoracic and abdominal aorta. Concomitant with this, the atherosclerosis phenotype of DKO mice was manifested as follows: (1) a profoundly enhanced immune cell infiltration; (2) significantly increased expression of inflammatory markers; (3) heightened reactive oxygen species generation. Next, to address the cellular contributor(s) within or outside of the vessel wall responsible for the atherosclerosis phenotype, we performed reciprocal bone marrow transplantation (BMT) experiments. Transplantation of DKO bone marrow to ApoE-/- mice resulted in an increase of atherosclerosis formation, while transplantation of ApoE-/- marrow to DKO mice caused a reduction of atherosclerosis. These results indicate CCN3 deficiency in the bone marrow plays a major role in the development of atherosclerosis. Mechanistically, our cell-based studies in isolated macrophages demonstrated that CCN3 deficiency leads to an increase of lipid uptake and foam cell formation, an effect attributed to the modulation of key factors (e.g., increase of CD36, decrease of ABCG1) involved in lipoprotein transport. Conclusion: These results demonstrate bone marrow-derived CCN3 as an essential regulator of atherosclerosis and suggest the potential for future therapeutic strategies by manipulating CCN3 levels.

Pathways of smooth muscle foam cell formation in atherosclerosis

2019 ◽  
Vol 30 (2) ◽  
pp. 117-124 ◽  
Author(s):  
Collin S. Pryma ◽  
Carleena Ortega ◽  
Joshua A. Dubland ◽  
Gordon A. Francis
Keyword(s):  
Smooth Muscle ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation

Mindin deficiency in macrophages protects against foam cell formation and atherosclerosis by targeting LXR-β

2018 ◽  
Vol 132 (11) ◽  
pp. 1199-1213 ◽  
Author(s):  
Cheng Zhang ◽  
Juan-Juan Qin ◽  
Fu-Han Gong ◽  
Jing-Jing Tong ◽  
Wen-Lin Cheng ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Matrix Protein ◽  
Foam Cell ◽  
Cell Formation ◽  
Direct Interaction ◽  
Extracellular Matrix Protein ◽  
Mechanistic Study ◽  
Foam Cell Formation ◽  
Atheromatous Plaques ◽  
Inflammatory Processes

Mindin, which is a highly conserved extracellular matrix protein, has been documented to play pivotal roles in regulating angiogenesis, inflammatory processes, and immune responses. The aim of the present study was to assess whether mindin contributes to the development of atherosclerosis. A significant up-regulation of Mindin expression was observed in the serum, arteries and atheromatous plaques of ApoE−/− mice after high-fat diet treatment. Mindin−/−ApoE−/− mice and macrophage-specific mindin overexpression in ApoE−/− mice (Lyz2-mindin-TG) were generated to evaluate the effect of mindin on the development of atherosclerosis. The Mindin−/−ApoE−/− mice exhibited significantly ameliorated atherosclerotic burdens in the entire aorta and aortic root and increased atherosclerotic plaque stability. Moreover, bone marrow transplantation further demonstrated that mindin deficiency in macrophages was largely responsible for the alleviated atherogenesis. The Lyz2-mindin-TG mice exhibited the opposite phenotype. Mindin deficiency enhanced foam cell formation by increasing the expression of cholesterol effectors, including ABCA1 and ABCG1. The mechanistic study indicated that mindin ablation promoted LXR-β expression via a direct interaction. Importantly, LXR-β inhibition largely reversed the ameliorating effect of mindin deficiency on foam cell formation and ABCA1 and ABCG1 expression. The present study demonstrated that mindin deficiency serves as a novel mediator that protects against foam cell formation and atherosclerosis by directly interacting with LXR-β.

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