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.

KRP-203, Sphingosine 1-Phosphate Receptor Type 1 Agonist, Ameliorates Atherosclerosis in LDL-R-/- Mice / Poti', Francesco; Gualtieri, Fabio; Sacchi, Sandro; Weißen Plenz, G; Varga, G; Brodde, M; Weber, C; Simoni, Manuela; Nofer, Jr. - In: ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY. - ISSN 1079-5642. - STAMPA. - 33:7(2013), pp. 1505-1512. [10.1161/ATVBAHA.113.301347]

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

POTI', FRANCESCO;GUALTIERI, FABIO;SACCHI, SANDRO;SIMONI, Manuela;
2013

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.
2013
33
7
1505
1512
KRP-203, Sphingosine 1-Phosphate Receptor Type 1 Agonist, Ameliorates Atherosclerosis in LDL-R-/- Mice / Poti', Francesco; Gualtieri, Fabio; Sacchi, Sandro; Weißen Plenz, G; Varga, G; Brodde, M; Weber, C; Simoni, Manuela; Nofer, Jr. - In: ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY. - ISSN 1079-5642. - STAMPA. - 33:7(2013), pp. 1505-1512. [10.1161/ATVBAHA.113.301347]
Poti', Francesco; Gualtieri, Fabio; Sacchi, Sandro; Weißen Plenz, G; Varga, G; Brodde, M; Weber, C; Simoni, Manuela; Nofer, Jr
File in questo prodotto:
File Dimensione Formato  
148.pdf

Solo gestori archivio

Descrizione: Articolo principale
Tipologia: Versione pubblicata dall'editore
Dimensione 1.53 MB
Formato Adobe PDF
1.53 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/963244
Citazioni
  • ???jsp.display-item.citation.pmc??? 30
  • Scopus 50
  • ???jsp.display-item.citation.isi??? 48
social impact