Title | Sphingosine-1-phosphate receptor-2 function in myeloid cells regulates vascular inflammation and atherosclerosis. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Skoura A, Michaud J, Im D-S, Thangada S, Xiong Y, Smith JD, Hla T |
Journal | Arterioscler Thromb Vasc Biol |
Volume | 31 |
Issue | 1 |
Pagination | 81-5 |
Date Published | 2011 Jan |
ISSN | 1524-4636 |
Keywords | Animals, Aortic Diseases, Apolipoproteins E, Atherosclerosis, Bone Marrow Transplantation, Disease Models, Animal, Endotoxins, Inflammation, Inflammation Mediators, Interleukin-18, Interleukin-1beta, Lipids, Lipoproteins, Lipoproteins, LDL, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Pyrazoles, Pyridines, Receptors, Lysosphingolipid, Sphingosine-1-Phosphate Receptors |
Abstract | OBJECTIVE: Sphingomyelin deposition and metabolism occurs in the atherosclerotic plaque, leading to the formation of sphingosine-1-phosphate (S1P), which activates G protein-coupled receptors to regulate vascular and immune cells. The role of S1P receptors in atherosclerosis has not been examined. METHODS AND RESULTS: We tested the hypothesis that S1P receptor-2 (S1PR2) regulates atherosclerosis. Apoe(-/-) S1pr2(-/-) mice showed greatly attenuated atherosclerosis compared with the Apoe(-/-) mice. Bone marrow transplant experiments indicate that S1PR2 function in the hematopoietic compartment is critical. S1PR2 is expressed in bone marrow-derived macrophages and in macrophage-like foam cells in atherosclerotic plaques. Reduced macrophage-like foam cells were found in the atherosclerotic plaques of Apoe(-/-)S1pr2(-/-) mice, suggesting that S1PR2 retains macrophages in atherosclerotic plaques. Lipoprotein profiles, plasma lipids, and oxidized low-density lipoprotein uptake by bone marrow-derived macrophages were not altered by the S1pr2 genotype. In contrast, endotoxin-induced inflammatory cytokine (interleukin [IL]-1β, IL-18) levels in the serum of S1PR2 knockout mice were significantly reduced. Furthermore, treatment of wild-type mice with S1PR2 antagonist JTE-013 suppressed IL-1β and IL-18 levels in plasma. CONCLUSIONS: These data suggest that S1PR2 signaling in the plaque macrophage regulates macrophage retention and inflammatory cytokine secretion, thereby promoting atherosclerosis. |
DOI | 10.1161/ATVBAHA.110.213496 |
Alternate Journal | Arterioscler Thromb Vasc Biol |
PubMed ID | 20947824 |
PubMed Central ID | PMC3013369 |
Grant List | R01 HL089934-04 / HL / NHLBI NIH HHS / United States HL70694 / HL / NHLBI NIH HHS / United States R37 HL067330-10 / HL / NHLBI NIH HHS / United States P01 HL070694 / HL / NHLBI NIH HHS / United States R37 HL067330 / HL / NHLBI NIH HHS / United States P01 HL070694-08 / HL / NHLBI NIH HHS / United States R01 HL067330 / HL / NHLBI NIH HHS / United States HL89934 / HL / NHLBI NIH HHS / United States HL67330 / HL / NHLBI NIH HHS / United States R01 HL089934 / HL / NHLBI NIH HHS / United States |
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