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

Francesco Potì; Martine Bot; Sara Costa; Valeria Bergonzini; Lynn Maines; Georg Varga; Hendrik Freise; Horst Robenek; Manuela Simoni; Jerzy-Roch Nofer

doi:10.1160/TH11-08-0583

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2012; 107(03): 552-561
DOI: 10.1160/TH11-08-0583

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

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

Francesco Potì

¹Department of Medicine, Endocrinology, Metabolism and Geriatrics, University of Modena and Reggio Emilia, Modena, Italy

,

Martine Bot

²Division of Biopharmaceutics, Gorlaeus Leiden/ Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Leiden, The Netherlands

,

Sara Costa

¹Department of Medicine, Endocrinology, Metabolism and Geriatrics, University of Modena and Reggio Emilia, Modena, Italy

,

Valeria Bergonzini

¹Department of Medicine, Endocrinology, Metabolism and Geriatrics, University of Modena and Reggio Emilia, Modena, Italy

,

Lynn Maines

³Apogee Biotechnology Corporation, Hershey, Pennsylvania, USA

,

Georg Varga

⁴Institute of Immunology, University of Münster, Münster, Germany

,

Hendrik Freise

⁵Department of Anaesthesiology and Intensive Medicine, University Hospital Münster, Münster, Germany

,

Horst Robenek

⁶Leibniz-Institute for Arteriosclerosis Research, University of Münster, Münster, Germany

,

Manuela Simoni^*

¹Department of Medicine, Endocrinology, Metabolism and Geriatrics, University of Modena and Reggio Emilia, Modena, Italy

,

Jerzy-Roch Nofer^*

¹Department of Medicine, Endocrinology, Metabolism and Geriatrics, University of Modena and Reggio Emilia, Modena, Italy

⁷Center for Laboratory Medicine, University Hospital Münster, Münster, Germany

› Author Affiliations

Abstract

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

Full Text

References

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