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.

scholarly journals Legumain Promotes Atherosclerotic Vascular Remodeling

2019 ◽  
Vol 20 (9) ◽  
pp. 2195 ◽  
Author(s):  
Nana Ozawa ◽  
Yuki Sato ◽  
Yukari Mori ◽  
Hiroko Masuda ◽  
Mao Yamane ◽  
...  
Keyword(s):  
Vascular Remodeling ◽  
Matrix Protein ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Foam Cell ◽  
Umbilical Vein ◽  
Cell Formation ◽  
Extracellular Matrix Protein ◽  
Foam Cell Formation ◽  
Atheromatous Plaques

Legumain, a recently discovered cysteine protease, is increased in both carotid plaques and plasma of patients with carotid atherosclerosis. Legumain increases the migration of human monocytes and human umbilical vein endothelial cells (HUVECs). However, the causal relationship between legumain and atherosclerosis formation is not clear. We assessed the expression of legumain in aortic atheromatous plaques and after wire-injury-induced femoral artery neointimal thickening and investigated the effect of chronic legumain infusion on atherogenesis in Apoe−/− mice. We also investigated the associated cellular and molecular mechanisms in vitro, by assessing the effects of legumain on inflammatory responses in HUVECs and THP-1 monocyte-derived macrophages; macrophage foam cell formation; and migration, proliferation, and extracellular matrix protein expression in human aortic smooth muscle cells (HASMCs). Legumain was expressed at high levels in atheromatous plaques and wire injury-induced neointimal lesions in Apoe−/− mice. Legumain was also expressed abundantly in THP-1 monocytes, THP-1 monocyte-derived macrophages, HASMCs, and HUVECs. Legumain suppressed lipopolysaccharide-induced mRNA expression of vascular cell adhesion molecule-1 (VCAM1), but potentiated the expression of interleukin-6 (IL6) and E-selectin (SELE) in HUVECs. Legumain enhanced the inflammatory M1 phenotype and oxidized low-density lipoprotein-induced foam cell formation in macrophages. Legumain did not alter the proliferation or apoptosis of HASMCs, but it increased their migration. Moreover, legumain increased the expression of collagen-3, fibronectin, and elastin, but not collagen-1, in HASMCs. Chronic infusion of legumain into Apoe−/− mice potentiated the development of atherosclerotic lesions, accompanied by vascular remodeling, an increase in the number of macrophages and ASMCs, and increased collagen-3 expression in plaques. Our study provides the first evidence that legumain contributes to the induction of atherosclerotic vascular remodeling.

scholarly journals ‘Blow my mind(in)’ – mindin neutralization for the prevention of atherosclerosis?

2018 ◽  
Vol 132 (14) ◽  
pp. 1509-1512
Author(s):  
Neil MacRitchie ◽  
Pasquale Maffia
Keyword(s):  
Vessel Wall ◽  
Cholesterol Efflux ◽  
Matrix Protein ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Extracellular Matrix Protein ◽  
Foam Cell Formation ◽  
Protective Effects ◽  
Inflammatory Microenvironment

The hallmark features of atherosclerosis include accumulation of low-density lipoprotein (LDL) carrying cholesterol in the vessel wall, formation of lipid-laden foam cells, and the creation of a pro-inflammatory microenvironment. To date, no effective treatments are clinically available for increasing cholesterol efflux from vascular macrophages and inducing reverse cholesterol transport (RCT). In an article published recently in Clinical Science (vol 132, issue 6, 1199-1213), Zhang and colleagues identified the extracellular matrix protein mindin/spondin 2 as a positive regulator of atherosclerosis. Genetic knockout of mindin in apolipoprotein-E (apoE)−/− mice attenuated atherosclerosis, foam cell formation, and inflammation within the vessel wall. Conversely, selective overexpression of mindin in macrophages in apoE−/− mice was sufficient to promote the greater severity of atherosclerosis. Interestingly, foam cell formation was closely associated with the expression of cholesterol transporters (ABCA1 and ACBG1) that facilitate cholesterol efflux. Liver X receptor (LXR)-β is a key modulator of cholesterol transporter expression and formed direct interactions with mindin. Furthermore, the protective effects of mindin deficiency on foam cell formation were blocked by inhibition of LXR-β. This article highlights a novel role of mindin in modulating foam cell formation and atherosclerosis development in mice through direct regulation of LXR-β. Thus far, direct targetting of LXR-β via pharmacological agonists has proven to be problematic due to the lack of subtype selective inhibitors and associated adverse effects. Indirect targetting of LXR-β, therefore, via mindin inhibition offers a new therapeutic strategy for increasing LXR-β induced cholesterol efflux, reducing foam cell formation, and preventing or treating atherosclerosis.

Pu-erh Tea Extract Attenuates Nicotine-Induced Foam Cell Formation in Primary Cultured Monocytes: An in Vitro Mechanistic Study

2016 ◽  
Vol 64 (16) ◽  
pp. 3186-3195 ◽  
Author(s):  
Shih-Hsin Tu ◽  
Ming-Yao Chen ◽  
Li-Ching Chen ◽  
Yi-Ting Mao ◽  
Chi-Hou Ho ◽  
...  
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Mechanistic Study ◽  
Foam Cell Formation ◽  
Tea Extract

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.

scholarly journals Chondroitin Sulphate Attenuates Atherosclerosis in ApoE Knockout Mice Involving Cellular Regulation of the Inflammatory Response

2018 ◽  
Vol 118 (07) ◽  
pp. 1329-1339 ◽  
Author(s):  
Pedro Melgar-Lesmes ◽  
Alvaro Sánchez-Herrero ◽  
Ferran Lozano-Juan ◽  
Jose de la Torre Hernández ◽  
Eulàlia Montell ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Adhesion Molecule ◽  
Knockout Mice ◽  
Foam Cell ◽  
Chondroitin Sulphate ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Therapeutic Effects ◽  
Atheromatous Plaques ◽  
Apoe Knockout Mice

AbstractChondroitin sulphate (CS) has long been used to treat osteoarthritis. Some investigations have also shown that the treatment with CS could reduce coronary events in patients with heart disease but no studies have identified the mechanistic role of these therapeutic effects. We aimed to investigate how the treatment with CS can interfere with the progress of atherosclerosis. The aortic arch, thoracic aorta and serum were obtained from apolipoprotein E (ApoE) knockout mice fed for 10 weeks with high-fat diet and then treated with CS (300 mg/kg, n = 15) or vehicle (n = 15) for 4 weeks. Atheromatous plaques were highlighted in aortas with Oil Red staining and analysed by microscopy. ApoE knockout mice treated with CS exhibited attenuated atheroma lesion size by 68% as compared with animals receiving vehicle. Serum lipids, glucose and C-reactive protein were not affected by treatment with CS. To investigate whether CS locally affects the inflamed endothelium or the formation of foam cells in plaques, human endothelial cells and monocytes were stimulated with tumour necrosis factor α or phorbol myristate acetate in the presence or absence of CS. CS reduced the expression of vascular cell adhesion molecule 1, intercellular adhesion molecule 1 and ephrin-B2 and improved the migration of inflamed endothelial cells. CS inhibited foam cell formation in vivo and concomitantly CD36 and CD146 expression and oxidized low-density lipoprotein uptake and accumulation in cultured activated human monocytes and macrophages. Reported cardioprotective effects of CS may arise from modulation of pro-inflammatory activation of endothelium and monocytes and foam cell formation.

scholarly journals Emerging Roles of Cardiotrophin-1 in the Pathogenesis and Biomarker of Atherosclerosis

J ◽  
2018 ◽  
Vol 1 (1) ◽  
pp. 94-105 ◽  
Author(s):  
Takuya Watanabe ◽  
Hanae Konii ◽  
Kengo Sato
Keyword(s):  
Heart Failure ◽  
Heart Disease ◽  
Cardiac Hypertrophy ◽  
Foam Cell ◽  
Vascular Endothelial Cells ◽  
Cell Formation ◽  
Hypertensive Heart Disease ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Atheromatous Plaques

Cardiotrophin-1 (CT-1), an interleukin-6 family cytokine, is known as an active inducer capable of cardiac hypertrophy and vascular stiffness in hypertensive heart disease. CT-1 is expressed at high levels in the heart, vascular endothelial cells (ECs), and adipocytes. CT-1 stimulates inflammatory and proatherogenic molecule expression in human monocytes and ECs, as well as monocyte-EC adhesion. CT-1 enhances oxidized low-density lipoprotein-induced foam-cell formation in human monocyte-derived macrophages. CT-1 stimulates the migration, proliferation, and colloagen-1 production in human vascular smooth muscle cells. Chronic CT-1 infusion into Apoe−/− mice accelerates the development of aortic atherosclerotic lesions. CT-1 is expressed at high levels in ECs and macrophage foam cells within atheromatous plaques in Apoe−/− mice. A blockade of CT-1 using anti-CT-1 neutralizing antibody results in the prevention of atherogenesis in Apoe−/− mice. Plasma CT-1 concentrations are elevated in patients with hypertensive heart disease, ischemic heart disease, and metabolic syndrome, and are positively associated with the severity of cardiac hypertrophy, heart failure, and atherosclerosis. Increased plasma concentration of CT-1 is a predictor of death and heart failure following acute myocardial infarction. Therefore, CT-1 serves a novel therapeutic target for atherosclerosis and related diseases. Plasma CT-1 may be a reliable biomarker for atherosclerotic cardiovascular diseases.

scholarly journals A Snake Venom-Secreted Phospholipase A2Induces Foam Cell Formation Depending on the Activation of Factors Involved in Lipid Homeostasis

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Elbio Leiguez ◽  
Karina Cristina Giannotti ◽  
Mariana do Nascimento Viana ◽  
Márcio Hideki Matsubara ◽  
Cristina Maria Fernandes ◽  
...  
Keyword(s):  
Protein Expression ◽  
Snake Venom ◽  
Foam Cell ◽  
Cell Formation ◽  
Lipid Homeostasis ◽  
Foam Cell Formation ◽  
Related Factors ◽  
Protein Levels ◽  
Inflammatory Processes ◽  
Functional Features

MT-III, a snake venom GIIA sPLA2, which shares structural and functional features with mammalian GIIA sPLA2s, activates macrophage defense functions including lipid droplet (LDs) formation, organelle involved in both lipid metabolism and inflammatory processes. Macrophages (MΦs) loaded with LDs, termed foam cells, characterize early blood vessel fatty-streak lesions during atherosclerosis. However, the factors involved in foam cell formation induced by a GIIA sPLA2are still unknown. Here, we investigated the participation of lipid homeostasis-related factors in LD formation induced by MT-III in macrophages. We found that MT-III activated PPAR-γand PPAR-β/δand increased the protein levels of both transcription factors and CD36 in macrophages. Pharmacological interventions evidenced that PPAR-γ, PPAR-β/δ, and CD36 as well as the endoplasmic reticulum enzymes ACAT and DGAT are essential for LD formation. Moreover, PPAR-β/δ, but not PPAR-γ, is involved in MT-III-induced PLIN2 protein expression, and both PPAR-β/δand PPAR-γupregulated CD36 protein expression, which contributes to MT-III-induced COX-2 expression. Furthermore, production of 15-d-PGJ2, an activator of PPARs, induced by MT-III, was dependent on COX-1 being LDs an important platform for generation of this mediator.

scholarly journals β-Endorphin Mediates the Development and Instability of Atherosclerotic Plaques

2020 ◽  
Vol 2020 ◽  
pp. 1-11 ◽  
Author(s):  
Taisuke Okano ◽  
Kengo Sato ◽  
Remina Shirai ◽  
Tomomi Seki ◽  
Koichiro Shibata ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Opioid Receptor ◽  
Adhesion Molecule ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Monocyte Adhesion ◽  
Endogenous Opioid Peptide ◽  
Atheromatous Plaques

β-Endorphin, an endogenous opioid peptide, and its μ-opioid receptor are expressed in brain, liver, and peripheral tissues. β-Endorphin induces endothelial dysfunction and is related to insulin resistance. We clarified the effects of β-endorphin on atherosclerosis. We assessed the effects of β-endorphin on the inflammatory response and monocyte adhesion in human umbilical vein endothelial cells (HUVECs), foam cell formation, and the inflammatory phenotype in THP-1 monocyte-derived macrophages, and migration and proliferation of human aortic smooth muscle cells (HASMCs) in vitro. We also assessed the effects of β-endorphin on aortic lesions in Apoe−/− mice in vivo. The μ-opioid receptor (OPRM1) was expressed in THP-1 monocytes, macrophages, HASMCs, HUVECs, and human aortic endothelial cells. β-Endorphin significantly increased THP-1 monocyte adhesion to HUVECs and induced upregulation of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin via nuclear factor-κB (NF-κB) and p38 phosphorylation in HUVECs. β-Endorphin significantly increased HUVEC proliferation and enhanced oxidized low-density lipoprotein-induced foam cell formation in macrophages. β-Endorphin also significantly shifted the macrophage phenotype to proinflammatory M1 rather than anti-inflammatory M2 via NF-κB phosphorylation during monocyte-macrophage differentiation and increased migration and apoptosis in association with c-jun-N-terminal kinase, p38, and NF-κB phosphorylation in HASMCs. Chronic β-endorphin infusion into Apoe−/− mice significantly aggravated the development of aortic atherosclerotic lesions, with an increase in vascular inflammation and the intraplaque macrophage/smooth muscle cell ratio, an index of plaque instability. Our study provides the first evidence that β-endorphin contributes to the acceleration of the progression and instability of atheromatous plaques. Thus, μ-opioid receptor antagonists may be useful for the prevention and treatment of atherosclerosis.

Chemerin-9, a potent agonist of chemerin receptor (ChemR23), prevents atherogenesis

2019 ◽  
Vol 133 (16) ◽  
pp. 1779-1796 ◽  
Author(s):  
Kengo Sato ◽  
Hayami Yoshizawa ◽  
Tomomi Seki ◽  
Remina Shirai ◽  
Tomoyuki Yamashita ◽  
...  
Keyword(s):  
Coronary Arteries ◽  
Foam Cell ◽  
Umbilical Vein ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Macrophage Foam Cell ◽  
Tnf Α ◽  
Atheromatous Plaques

Abstract Plasma levels of chemerin, an adipocytokine produced from the adipose tissues and liver, are associated with metabolic syndrome and coronary artery disease (CAD). Chemerin and its analog, chemerin-9, are known to bind to their receptor, ChemR23. However, whether chemerin and chemerin-9 affect atherogenesis remains to be elucidated. We investigated the expression of chemerin and ChemR23 in human coronary arteries and cultured human vascular cells. The effects of chemerin and chemerin-9 on atheroprone phenomena were assessed in human THP1 monocytes, human umbilical vein endothelial cells (HUVECs), and human aortic smooth muscle cells (HASMCs) and aortic lesions in Apoe−/− mice. In patients with CAD, a small amount of ChemR23, but not chemerin, was expressed within atheromatous plaques in coronary arteries. Chemerin and ChemR23 were expressed at high levels in THP1 monocytes, THP1-derived macrophages, and HUVECs; however, their expression in HASMCs was weak. Chemerin and chemerin-9 significantly suppressed the tumor necrosis factor-α (TNF-α)-induced mRNA expression of adhesion and pro-inflammatory molecules in HUVECs. Chemerin and chemerin-9 significantly attenuated the TNF-α-induced adhesion of THP1 monocytes to HUVECs and macrophage inflammatory phenotype. Chemerin and chemerin-9 suppressed oxidized low-density lipoprotein (oxLDL)-induced macrophage foam cell formation associated with down-regulation of CD36 and up-regulation of ATP-binding cassette transporter A1 (ABCA1). In HASMCs, chemerin and chemerin-9 significantly suppressed migration and proliferation without inducing apoptosis. In the Apoe−/− mice, a 4-week infusion of chemerin-9 significantly decreased the areas of aortic atherosclerotic lesions by reducing intraplaque macrophage and SMC contents. Our results indicate that chemerin-9 prevents atherosclerosis. Therefore, the development of chemerin analogs/ChemR23 agonists may serve as a novel therapeutic target for atherosclerotic diseases.

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.

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