jte-013 and Atherosclerosis

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.. 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.. These data suggest that S1PR2 signaling in the plaque macrophage regulates macrophage retention and inflammatory cytokine secretion, thereby promoting atherosclerosis.

Topics: 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