Metformin inhibits monocyte adhesion to endothelial cells and foam cell formation

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.

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Pharmacological inhibition of EZH2 by GSK126 decreases atherosclerosis by modulating foam cell formation and monocyte adhesion in apolipoprotein E‑deficient mice

Experimental and Therapeutic Medicine ◽

10.3892/etm.2021.10273 ◽

2021 ◽

Vol 22 (2) ◽

Author(s):

Xianjing Wei ◽

Ying Zhang ◽

Lianna Xie ◽

Kaijun Wang ◽

Xiaoqing Wang

Keyword(s):

Apolipoprotein E ◽

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

Monocyte Adhesion ◽

Pharmacological Inhibition ◽

Deficient Mice

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TRAF5 Deficiency Accelerates Atherogenesis in Mice by Increasing Inflammatory Cell Recruitment and Foam Cell Formation

Circulation Research ◽

10.1161/circresaha.110.219295 ◽

2010 ◽

Vol 107 (6) ◽

pp. 757-766 ◽

Cited By ~ 34

Author(s):

Anna Missiou ◽

Philipp Rudolf ◽

Peter Stachon ◽

Dennis Wolf ◽

Nerea Varo ◽

...

Keyword(s):

Endothelial Cells ◽

Inflammatory Cell ◽

Foam Cell ◽

Interleukin 1 ◽

Cell Formation ◽

Foam Cell Formation ◽

High Cholesterol Diet ◽

Cell Recruitment ◽

Inflammatory Cell Recruitment

Rationale: Tumor necrosis factor receptor–associated factors (TRAFs) are cytoplasmic adaptor proteins for the TNF/interleukin-1/Toll-like receptor superfamily. Ligands of this family comprise multiple important cytokines such as TNFα, CD40L, and interleukin-1β that promote chronic inflammatory diseases such as atherosclerosis. We recently reported overexpression of TRAF5 in murine and human atheromata and that TRAF5 promotes inflammatory functions of cultured endothelial cells and macrophages. Objective: This study tested the hypothesis that TRAF5 modulates atherogenesis in vivo. Methods and Results: Surprisingly, TRAF5 −/− /LDLR −/− mice consuming a high-cholesterol diet for 18 weeks developed significantly larger atherosclerotic lesions than did TRAF5 +/+ /LDLR −/− controls. Plaques of TRAF5-deficient animals contained more lipids and macrophages, whereas smooth muscle cells and collagen remained unchanged. Deficiency of TRAF5 in endothelial cells or in leukocytes enhanced adhesion of inflammatory cells to the endothelium in dynamic adhesion assays in vitro and in murine vessels imaged by intravital microscopy in vivo. TRAF5 deficiency also increased expression of adhesion molecules and chemokines and potentiated macrophage lipid uptake and foam cell formation. These findings coincided with increased activation of JNK and appeared to be independent of TRAF2. Finally, patients with stable or acute coronary heart disease had significantly lower amounts of TRAF5 mRNA in blood compared with healthy controls. Conclusions: Unexpectedly, TRAF5 deficiency accelerates atherogenesis in mice, an effect likely mediated by increased inflammatory cell recruitment to the vessel wall and enhanced foam cell formation.

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

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657753 ◽

2018 ◽

Vol 118 (07) ◽

pp. 1329-1339 ◽

Cited By ~ 6

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.

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Salusin-β induces foam cell formation and monocyte adhesion in human vascular smooth muscle cells via miR155/NOX2/NFκB pathway

Scientific Reports ◽

10.1038/srep23596 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 21

Author(s):

Hai-Jian Sun ◽

Ming-Xia Zhao ◽

Tong-Yan Liu ◽

Xing-Sheng Ren ◽

Qi Chen ◽

...

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Foam Cell ◽

Cell Formation ◽

Muscle Cells ◽

Foam Cell Formation ◽

Monocyte Adhesion ◽

Nfκb Pathway

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Role of Ox-LDL and LOX-1 in Atherogenesis

Current Medicinal Chemistry ◽

10.2174/0929867325666180508100950 ◽

2019 ◽

Vol 26 (9) ◽

pp. 1693-1700 ◽

Cited By ~ 28

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.

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THE SCAVENGER RECEPTOR SR-PSOX/CXCL16 INFLUENCE FOAM CELL FORMATION AND ADHESION OF MONOCYTES TO ENDOTHELIAL CELLS

Atherosclerosis Supplements ◽

10.1016/s1567-5688(08)70258-7 ◽

2008 ◽

Vol 9 (1) ◽

pp. 65

Author(s):

O. Hofnagel ◽

I. uers ◽

G. Weissen-Plenz ◽

H. Robenek

Keyword(s):

Endothelial Cells ◽

Foam Cell ◽

Scavenger Receptor ◽

Cell Formation ◽

Foam Cell Formation

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Low-Density Lipoprotein Modified by Myeloperoxidase in Inflammatory Pathways and Clinical Studies

Mediators of Inflammation ◽

10.1155/2013/971579 ◽

2013 ◽

Vol 2013 ◽

pp. 1-18 ◽

Cited By ~ 42

Author(s):

Cédric Delporte ◽

Pierre Van Antwerpen ◽

Luc Vanhamme ◽

Thierry Roumeguère ◽

Karim Zouaoui Boudjeltia

Keyword(s):

Endothelial Cells ◽

Foam Cell ◽

Thrombus Formation ◽

Low Density Lipoprotein ◽

Cell Formation ◽

Density Lipoprotein ◽

Ldl Oxidation ◽

Foam Cell Formation ◽

Low Density ◽

Oxidized Lipoproteins

Oxidation of low-density lipoprotein (LDL) has a key role in atherogenesis. Among the different models of oxidation that have been studied, the one using myeloperoxidase (MPO) is thought to be more physiopathologically relevant. Apolipoprotein B-100 is the unique protein of LDL and is the major target of MPO. Furthermore, MPO rapidly adsorbs at the surface of LDL, promoting oxidation of amino acid residues and formation of oxidized lipoproteins that are commonly named Mox-LDL. The latter is not recognized by the LDL receptor and is accumulated by macrophages. In the context of atherogenesis, Mox-LDL accumulates in macrophages leading to foam cell formation. Furthermore, Mox-LDL seems to have specific effects and triggers inflammation. Indeed, those oxidized lipoproteins activate endothelial cells and monocytes/macrophages and induce proinflammatory molecules such as TNFαand IL-8. Mox-LDL may also inhibit fibrinolysis mediated via endothelial cells and consecutively increase the risk of thrombus formation. Finally, Mox-LDL has been involved in the physiopathology of several diseases linked to atherosclerosis such as kidney failure and consequent hemodialysis therapy, erectile dysfunction, and sleep restriction. All these issues show that the investigations of MPO-dependent LDL oxidation are of importance to better understand the inflammatory context of atherosclerosis.

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