Inhibition of monocyte chemotaxis by VB-201, a small molecule lecinoxoid, hinders atherosclerosis development in ApoE−/− mice
| Autor: | Erez Feige, Jacob George, Dror Harats, Omri Polonsky, Eyal Breitbart, Ravit Hait-Darshan, Oshrat Propheta-Meiran, Itzhak Mendel, Anat Shoham, Yaniv Salem, Niva Yacov, Itzhak Levi |
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| Rok vydání: | 2013 |
| Předmět: |
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Vasculitis Cell signaling Monocyte chemotaxis Phagocytosis Inflammation Peritonitis CCL2 Biology Monocytes Mice Oxidized phospholipids Apolipoproteins E medicine Animals Humans Cells Cultured Triglycerides Mice Knockout Chemotaxis Monocyte Atherosclerosis Flow Cytometry Glycerylphosphorylcholine Cell biology Mice Inbred C57BL Disease Models Animal Cholesterol medicine.anatomical_structure Biochemistry Lecinoxoids Female Receptors Chemokine Signal transduction medicine.symptom Cardiology and Cardiovascular Medicine Signal Transduction |
| Zdroj: | Atherosclerosis. 229(2):430-439 |
| ISSN: | 0021-9150 |
| DOI: | 10.1016/j.atherosclerosis.2013.06.005 |
| Popis: | Objective Monocytes are motile cells which sense inflammatory stimuli and subsequently migrate to sites of inflammation. Key players in host defense, monocytes have nevertheless been implicated as requisite mediators of several chronic inflammatory diseases. Inhibition of monocyte chemotaxis is therefore an attractive anti-inflammatory strategy. Oxidized phospholipids (OxPL) are native regulators of inflammation, yet their direct effect on monocyte chemotaxis is poorly defined. In this study, we investigated the direct effect of natural and synthetic phospholipids on monocyte chemotaxis. Methods Exploring various phospholipids using in vitro chemotaxis assays, we found that the natural phospholipid 1-palmitoyl-2-glutaryl phosphatidylcholine (PGPC) can decrease monocyte chemotaxis by 50%, while other tested OxPL had no effect. We generated a library of synthetic OxPL designated lecinoxoids, which was screened for anti-inflammatory properties. Results and conclusions VB-201, a small-molecule lecinoxoid, exhibited up to 90% inhibition of monocyte chemotaxis in vitro . Molecular analysis revealed that the effect of VB-201 was not restricted to a specific chemotactic ligand or receptor, and resulted from inhibition of signaling pathways required for monocyte chemotaxis. Interestingly, VB-201 did not inhibit monocyte adhesion or phagocytosis and had no effect on chemotaxis of CD4 + T-cells or neutrophils. In vivo , oral treatment with VB-201 reduced monocyte migration in a peritonitis model and inhibited atheroma development in ApoE −/− mice, without affecting cholesterol or triglyceride levels. Our findings highlight a novel role played by native and synthetic phospholipids in regulation of monocyte chemotaxis. The data strengthen the involvement of phospholipids as key signaling molecules in inflammatory settings and demonstrate their potential therapeutic applicability. |
| Databáze: | OpenAIRE |
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