KRP-203, sphingosine 1-phosphate receptor type 1 agonist, ameliorates atherosclerosis in LDL-R-/- mice.

Abstract

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 (3.0 mg/kg per day; 6 and 16 weeks). KRP-203 substantially reduced atherosclerotic lesion formation without affecting plasma lipid concentrations. However, KRP-203 induced lymphopenia, reduced total (CD4(+), CD8(+)) and activated (CD69(+)/CD8(+), CD69(+)/CD4(+)) 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, respectively.

CONCLUSIONS:

Present results demonstrate that activation of S1P signaling pathways inhibit atherosclerosis by modulating lymphocyte and macrophage function and suggest that S1P receptor type 1 at least partially mediates antiatherogenic effects of S1P.

• Authors: Francesco Potì, Fabio Gualtieri, Sandro Sacchi, Gabriele Weißen-Plenz, Georg Varga, Martin Brodde, Christian Weber, Manuela Simoni, Jerzy-Roch Nofer
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 33 Issue 7 Pg. 1505-12 (Jul 2013) ISSN: 1524-4636 [Electronic] United States
• PMID: 23640484 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Cardiovascular Agents
• Inflammation Mediators
• KRP-203
• Lipids
• Receptors, LDL
• Receptors, Lysosphingolipid
• Sulfhydryl Compounds

Topics

• Animals
• Aorta (drug effects, immunology, metabolism, pathology)
• Aortic Diseases (genetics, immunology, metabolism, pathology, prevention & control)
• Atherosclerosis (genetics, immunology, metabolism, pathology, prevention & control)
• Biomarkers (blood)
• CD4-Positive T-Lymphocytes (drug effects, immunology)
• CD8-Positive T-Lymphocytes (drug effects, immunology)
• Cardiovascular Agents (pharmacology)
• Dendritic Cells (drug effects, immunology)
• Disease Models, Animal
• Endothelial Cells (drug effects, immunology)
• Humans
• Inflammation (genetics, immunology, metabolism, pathology, prevention & control)
• Inflammation Mediators (metabolism)
• Lipids (blood)
• Lymphocyte Activation (drug effects)
• Lymphopenia (immunology)
• Macrophage Activation (drug effects)
• Macrophages (drug effects, immunology)
• Mice
• Mice, Knockout
• Receptors, LDL (deficiency, genetics)
• Receptors, Lysosphingolipid (agonists, metabolism)
• Signal Transduction (drug effects)
• Sulfhydryl Compounds (pharmacology)
• U937 Cells