Sphingosine kinase inhibition exerts both pro- and anti-atherogenic effects in low-density lipoprotein receptor-deficient (LDL-R^−/−) mice

Summary

Sphingosine 1-phosphate (S1P), a lysosphingolipid associated with high-density lipoprotein (HDL), contributes to the anti-atherogenic potential attributed to this lipoprotein. This study examined whether a reduction of S1P plasma levels affects atherosclerosis in a murine model of disease. LDL-R^−/−mice on Western diet were given ABC294640, an inhibitor of sphingosine kinase (SphK) for 16 weeks. ABC294640 decreased plasma S1P by approximately 30%. However, ABC294640 failed to affect atherosclerotic lesion formation. Plasma triglycerides were reduced whereas total and HDL-cholesterol remained unchanged in course of ABC294640 treatment. ABC294640 increased plasma interleukin (IL)-12p70 and RANTES concentration as well as IL-12p70, RANTES and interferon (IFN)-γ production by peritoneal cells and this was paralleled by enhanced activity of peritoneal and spleen dendritic cells as evidenced by up-regulation of CD86 and MHC-II on CD11c⁺ cells. As a consequence, increased T-cell activation was noted in ABC294640-treated mice as indicated by enhanced CD4⁺ splenocyte proliferation, IFN-γ and IL-2 production, and CD69 expression. Con-comitantly, however, ABC294640 treatment redistributed CD4⁺ and CD8⁺ cells from blood to lymphatic organs and reduced T-cell number within atherosclerotic lesions. In addition, plasma sVCAM-1, sICAM-1, and MCP-1 levels as well as in vivo leukocyte adhesion and CCL19-induced T-cell penetration into peritoneum were lower in ABC294640-treated animals. In vitro experiments demonstrated reduced VCAM-1 and ICAM-1 expression and lymphocyte adhesion to endothelial cells exposed to ABC294640. In conclusion, treatment with SphK inhibitor leads to both pro- and anti-atherogenic effects in LDL-R^−/− mice. As a consequence, SphK inhibition fails to affect atherosclerosis despite significant S1P reduction in plasma.

Keywords

Sphingosine 1-phosphate - high density lipoproteins - inflammation - endothelium - animal models of atherosclerosis

^* These authors contributed equally.

• References

• 1 Strub GM, Maceyka M, Hait NC. et al. Extracellular and intracellular actions of sphingosine-1-phosphate. Adv Exp Med Biol 2010; 688: 141-155.
• 2 Zhang B, Tomura H, Kuwabara A. et al. Correlation of high density lipoprotein (HDL)-associated sphingosine 1-phosphate with serum levels of HDL-cholesterol and apolipoproteins. Atherosclerosis 2005; 178: 199-205.
• 3 Alemany R, van Koppen CJ, Danneberg K. et al. Regulation and functional roles of sphingosine kinases. Naunyn Schmiedebergs Arch Pharmacol 2007; 374: 413-428.
• 4 Takabe K, Paugh SW, Milstien S. et al. „Inside-out” signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol Rev 2008; 60: 181-195.
• 5 Rosen H, Gonzalez-Cabrera PJ, Sanna MG. et al. Sphingosine 1-phosphate receptor signaling. Annu Rev Biochem 2009; 78: 743-768.
• 6 Lucke S, Levkau B. Endothelial functions of sphingosine-1-phosphate. Cell Physiol Biochem 2010; 26: 87-96.
• 7 Igarashi J, Michel T. Sphingosine-1-phosphate and modulation of vascular tone. Cardiovasc Res 2009; 82: 212-220.
• 8 Cyster JG. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu Rev Immunol 2005; 23: 127-159.
• 9 Rivera J, Proia RL, Olivera A. The alliance of sphingosine-1-phosphate and its receptors in immunity. Nat Rev Immunol 2008; 08: 753-763.
• 10 Weigert A, Weis N, Brüne B. Regulation of macrophage function by sphingosine-1-phosphate. Immunobiology 2009; 214: 748-760.
• 11 Xia P, Gamble JR, Rye KA. et al. Tumor necrosis factor-alpha induces adhesion molecule expression through the sphingosine kinase pathway. Proc Natl Acad Sci USA 1998; 95: 14196-14201.
• 12 Zhi L, Leung BP, Melendez AJ. Sphingosine kinase 1 regulates pro-inflammatory responses triggered by TNFalpha in primary human monocytes. J Cell Physiol 2006; 208: 109-115.
• 13 Sattler KJ, Elbasan S, Keul P. et al. Sphingosine 1-phosphate levels in plasma and HDL are altered in coronary artery disease. Basic Res Cardiol 2010; 105: 821-832.
• 14 Argraves KM, Sethi AA, Gazzolo PJ. et al. S1P, dihydro-S1P and C24: 1-ceramide levels in the HDL-containing fraction of serum inversely correlate with occurrence of ischemic heart disease. Lipids Health Dis 2011; 10: 70.
• 15 Argraves KM, Argraves WS. HDL serves as a S1P signaling platform mediating a multitude of cardiovascular effects. J Lipid Res 2007; 48: 2325-2333.
• 16 Nofer JR. High-density lipoprotein, sphingosine 1-phosphate, and atherosclerosis. J Clin Lipidol 2008; 02: 4-11.
• 17 Rodríguez C, González-Díez M, Badimon L. et al. Sphingosine-1-phosphate: A bioactive lipid that confers high-density lipoprotein with vasculoprotection mediated by nitric oxide and prostacyclin. Thromb Haemost 2009; 101: 665-673.
• 18 González-Díez M, Rodríguez C, Badimon L. et al. Prostacyclin induction by highdensity lipoprotein (HDL) in vascular smooth muscle cells depends on sphingosine 1-phosphate receptors: effect of simvastatin. Thromb Haemost 2008; 100: 119-126.
• 19 Nofer JR, Bot M, Brodde M. et al. FTY720, a synthetic sphingosine 1 phosphate analogue, inhibits development of atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation 2007; 115: 501-508.
• 20 Keul P, Tölle M, Lucke S. et al. The sphingosine-1-phosphate analogue FTY720 reduces atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2007; 27: 607-613.
• 21 French KJ, Zhuang Y, Maines LW. et al. Pharmacology and antitumor activity of ABC294640, a selective inhibitor of sphingosine kinase-2. J Pharmacol Exp Ther 2010; 333: 129-139.
• 22 Maines LW, Fitzpatrick LR, French KJ. et al. Suppression of ulcerative colitis in mice by orally available inhibitors of sphingosine kinase. Dig Dis Sci 2008; 53: 997-1012.
• 23 Yusof M, Kamada K, Gaskin FS. et al. Angiotensin II mediates postischemic leukocyte-endothelial interactions: role of calcitonin gene-related peptide. Am J Physiol Heart Circ Physiol 2007; 292: H3032-H3037.
• 24 Nofer JR, van der M, Tölle M. et al. HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3. J Clin Invest 2004; 113: 569-581.
• 25 Varga G, Balkow S, Wild MK. et al. Active MAC-1 (CD11b/CD18) on DCs inhibits full T-cell activation. Blood 2007; 109: 661-669.
• 26 Maines LW, French KJ, Wolpert EB. et al. Pharmacologic manipulation of sphingosine kinase in retinal endothelial cells: implications for angiogenic ocular diseases. Invest Ophthalmol Vis Sci 2006; 47: 5022-5031.
• 27 Miyamoto T, Matsumori A, Hwang MW. et al. Therapeutic effects of FTY720, a new immunosuppressive agent, in a murine model of acute viral myocarditis. J Am Coll Cardiol 2001; 37: 1713-1718.
• 28 Peng X, Hassoun PM, Sammani S. et al. Protective effects of sphingosine 1-phosphate in murine endotoxin-induced inflammatory lung injury. Am J Respir Crit Care Med 2004; 169: 1245-1251.
• 29 Webb M, Tham CS, Lin FF. et al. Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice. J Neuroimmunol 2004; 153: 108-121.
• 30 Fujii R, Kanai T, Nemoto Y. et al. FTY720 suppresses CD4+CD44highCD62L- effector memory T cell-mediated colitis. Am J Physiol Gastrointest Liver Physiol 2006; 291: G267-G274.
• 31 Kharel Y, Lee S, Snyder AH. et al. Sphingosine kinase 2 is required for modulation of lymphocyte traffic by FTY720. J Biol Chem 2005; 280: 36865-36872.
• 32 Jun DJ, Lee JH, Choi BH. et al. Sphingosine-1-phosphate modulates both lipolysis and leptin production in differentiated rat white adipocytes. Endocrinology 2006; 147: 5835-5844.
• 33 Chi H, Flavell RA. Cutting edge: regulation of T cell trafficking and primary immune responses by sphingosine 1-phosphate receptor 1. J Immunol 2005; 174: 2485-2488.
• 34 Matloubian M, Lo CG, Cinamon G. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 2004; 427: 355-360.
• 35 Allende ML, Dreier JL, Mandala S. et al. Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration. J Biol Chem 2004; 279: 15396-15401.
• 36 Alfonso C, McHeyzer-Williams MG, Rosen H. CD69 down-modulation and inhibition of thymic egress by short- and long-term selective chemical agonism of sphingosine 1-phosphate receptors. Eur J Immunol 2006; 36: 149-159.
• 37 Jin Y, Knudsen E, Wang L. et al. Sphingosine 1-phosphate is a novel inhibitor of T-cell proliferation. Blood 2003; 101: 4909-4915.
• 38 Dorsam G, Graeler MH, Seroogy C. et al. Transduction of multiple effects of sphingosine 1-phosphate (S1P) on T cell functions by the S1P1 G protein-coupled receptor. J Immunol 2003; 171: 3500-3507.
• 39 Gräler MH, Huang MC, Watson S. et al. Immunological effects of transgenic constitutive expression of the type 1 sphingosine 1-phosphate receptor by mouse lymphocytes. J Immunol 2005; 174: 1997-2003.
• 40 Müller H, Hofer S, Kaneider N. et al. The immunomodulator FTY720 interferes with effector functions of human monocyte-derived dendritic cells. Eur J Immunol 2005; 35: 533-545.
• 41 Gollmann G, Neuwirt H, Tripp CH. et al. Sphingosine-1-phosphate receptor type-1 agonism impairs blood dendritic cell chemotaxis and skin dendritic cell migration to lymph nodes under inflammatory conditions. Int Immunol 2008; 20: 911-923.
• 42 Lan YY, Tokita D, Wang Z. et al. Sphingosine 1-phosphate receptor agonism impairs skin dendritic cell migration and homing to secondary lymphoid tissue: association with prolonged allograft survival. Transpl Immunol 2008; 20: 88-94.
• 43 Schröder M, Richter C, Juan MH. et al. The sphingosine kinase 1 and S1P1 axis specifically counteracts LPS-induced IL-12p70 production in immune cells of the spleen. Mol Immunol 2011; 48: 1139-1148.
• 44 Gotsman I, Sharpe AH, Lichtman AH. T-cell costimulation and coinhibition in atherosclerosis. Circ Res 2008; 103: 1220-1231.
• 45 Ait-Oufella H, Taleb S, Mallat Z. et al. Cytokine network and T cell immunity in atherosclerosis. Semin Immunopathol 2009; 31: 23-33.
• 46 Niessner A, Weyand CM. Dendritic cells in atherosclerotic disease. Clin Immunol 2010; 134: 25-32.
• 47 Wang L, Xing XP, Holmes A. et al. Activation of the sphingosine kinase-signaling pathway by high glucose mediates the proinflammatory phenotype of endothelial cells. Circ Res 2005; 97: 891-899.
• 48 Limaye V, Xia P, Hahn C. et al. Chronic increases in sphingosine kinase-1 activity induce a pro-inflammatory, pro-angiogenic phenotype in endothelial cells. Cell Mol Biol Lett 2009; 14: 424-441.
• 49 Tamama K, Okajima F. Sphingosine 1-phosphate signaling in atherosclerosis and vascular biology. Curr Opin Lipidol 2002; 13: 489-495.
• 50 Okajima F, Sato K, Kimura T. Anti-atherogenic actions of high-density lipoprotein through sphingosine 1-phosphate receptors and scavenger receptor class B type I. Endocr J 2009; 56: 317-334.