• Athanasia Skoura, Jason Michaud, Dong-Soon Im, Shobha Thangada, Yuquan Xiong, Jonathan D Smith, and Timothy Hla.
• Department of Pathology and Laboratory Medicine, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA.
• Arterioscler. Thromb. Vasc. Biol. 2011 Jan 1;31(1):81-5.

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

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