KRP-203, Sphingosine 1-Phosphate Receptor Type 1 Agonist, Ameliorates Atherosclerosis in LDL-R ^−/− Mice

Abstract

S phingosine 1-phosphate (S1P) is a pleiotropic lipid mediator produced by phosphorylation of sphingosine by sphingosine kinases 1 and 2 in response to a variety of stimuli.1,2 S1P interacts with 5 related G-protein-coupled receptors termed S1P receptor (S1PR) types 1 to 5, which regulate a wide spectrum of cellular functions, including proliferation and survival, cytoskeletal rearrangements, and cell motility, and exert potent cytoprotective effects. 3,4 In the vasculature, S1PR1, 2, and 3 were identified on endothelial surface, whereas S1PR2 and S1PR3 are present on smooth muscle cells. Through these receptors S1P is believed to provide essential contribution to the new vessel formation and the maintenance of vascular barrier integrity. 5,6 In addition, S1P was demonstrated to interfere with proliferation, migration, and activation of lymphocytes and monocytes/macrophages and to regulate their recruitment to sites of inflammation. 7-9 These immunomodulatory activities, which are mediated by S1PR1 and 4 on lymphocytes and S1PR1, 2, 3, and 4 on macrophages, likely account for beneficial effects exerted by S1P and its analogues in animal models of inflammatory diseases, such as ulcerating colitis, viral myocarditis, endotoxin-induced lung injury, or autoimmune encephalomyelitis. 10-13Erythrocytes and platelets are major sources of S1P in plasma, where it is associated with a subfraction(s) of high-density lipoprotein (HDL)-a potent plasma-borne antiatherogenic factor. [14][15][16] There is substantial evidence © 2013 American Heart Association, Inc. Objective-Sphingosine 1-phosphate (S1P) partly accounts for antiatherogenic properties of high-density lipoproteins. We previously demonstrated that FTY720, a synthetic S1P analog targeting all S1P receptors but S1P receptor type 2, inhibits murine atherosclerosis. Here, we addressed the identity of S1P receptor mediating atheroprotective effects of S1P. Approach and Results-Low-density lipoprotein receptor-deficient mice on cholesterol-rich diet were given selective S1P receptor type 1 agonist KRP-203 ( T cells in peripheral lymphoid organs, and interfered with lymphocyte function, as evidenced by decreased T-cell proliferation and interleukin-2 and interferon-γ production in activated splenocytes. Cyto-and chemokine (tumor necrosis factor-α, regulated and normal T cell expressed and secreted) levels in plasma and aortas were reduced by KRP-203 administration. Moreover, macrophages from KRP-203-treated mice showed reduced expression of activation marker MCH-II and poly(I:C)-elicited production of tumor necrosis factor-α, monocyte chemoattractant protein-1, and interleukin-6. In vitro studies demonstrated that KRP-203 reduced tumor necrosis factor-α, interleukin-6, and interferon-γ-induced protein-10 production; IκB and signal transducer and activator of transcription-1 phosphorylation; and nuclear factor κB and signal transducer and activator of transcription-1 activation in poly(I:C)-, lipopolysaccharide-, or interferon-γ-stimulated bone marrow macrophages, respec...

Fingolimod Attenuates Splenocyte-Induced Demyelination in Cerebellar Slice Cultures

“…Our analysis of these splenocyte cultures showed an approximate 60% lymphocyte population, of which more than 40% were CD4+ T cells. We note the cytokines analysed in our study, IL10, IL6, IFNγ and TNFα can be produce by cells other than CD4+ T cells, where S1PR activation has been shown to alter cytokine levels in, for example, macrophages (attenuating levels of TNFα, MCP1 and IL6) [42] and dendritic cells (reducing levels of IL12 and increasing IL10) [49]. Furthermore, pFTY720 treated dendritic cells show reduced ability to activate T cells, which in turn produce less IFNγ and more IL4 compared to when activated with untreated dendritic cells, indicating a shift from a pro-inflammatory Th1 to an anti-inflammatory Th2 [41], [49]–[50].…”

Survival benefit of sphingosin‐1‐phosphate and receptors expressions in breast cancer patients

“…KRP‐203 is a kind of S1PR1 selective agonists. It has been demonstrated to regulate both T and B cells and improve the outcome of atherosclerosis disease 55. SEW2871 is also a selective S1PR1 agonist and has been used to treat acute kidney injury and ischemia‐reperfusion injury in mice 56, 57.…”

Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy

“…The role of S1P in vascular and cardiac diseases is beginning to be appreciated but is not well understood. Several S1P receptor modulators were shown to reduce inflammatory responses and atherosclerosis in mouse models (115,116). S1P 2 is expressed in atherosclerotic plaques and contributes to macrophage content and inflammatory responses.…”