Thromb Haemost 2018; 118(08): 1470-1480
DOI: 10.1055/s-0038-1666870
Atherosclerosis and Ischaemic Disease
Georg Thieme Verlag KG Stuttgart · New York

Elevating Endogenous Sphingosine-1-Phosphate (S1P) Levels Improves Endothelial Function and Ameliorates Atherosclerosis in Low Density Lipoprotein Receptor-Deficient (LDL-R−/−) Mice

Renata Feuerborn*
1  Center for Laboratory Medicine, University Hospital Münster, University of Münster, Münster, Germany
,
Manuela Besser*
2  Department of Anaesthesiology and Intensive Medicine, University Hospital Münster, University of Münster, Münster, Germany
,
Francesco Potì
3  Department of Medicine and Surgery–Unit of Neurosciences, University of Parma, Parma, Italy
4  Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
,
Ralph Burkhardt
5  Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, University of Leipzig, Leipzig, Germany
,
Gabriele Weißen-Plenz
1  Center for Laboratory Medicine, University Hospital Münster, University of Münster, Münster, Germany
,
Uta Ceglarek
5  Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, University of Leipzig, Leipzig, Germany
,
Manuela Simoni
4  Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
,
Richard L. Proia
6  Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States
,
Hendrik Freise
2  Department of Anaesthesiology and Intensive Medicine, University Hospital Münster, University of Münster, Münster, Germany
,
Jerzy-Roch Nofer
1  Center for Laboratory Medicine, University Hospital Münster, University of Münster, Münster, Germany
› Author Affiliations
Funding Grant NO406/3–1 from Deutsche Forschungsgemeinschaft (DFG) to J.-R.N., grant NO110816 from the Innovative Medizinische Forschung (IMF) to J.-R.N., intramural resources of the Center for Laboratory Medicine to J.-R.N., FIRB-IDEAS grant RBID08777T from the Italian Ministry of Education, University and Research to J.-R.N. and M.S. and the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease to R.P.
Further Information

Publication History

16 January 2018

24 May 2018

Publication Date:
30 July 2018 (online)

Abstract

Background Sphingosine-1-phosphate (S1P) is a bioactive lysosphingolipid and a constituent of high-density lipoprotein (HDL) exerting several atheroprotective effects in vitro. However, the few studies addressing anti-atherogenic effects of S1P in vivo have led to disparate results. We here examined atherosclerosis development in low-density lipoprotein receptor (LDL-R)-deficient (LDL-R−/−) mice with elevated endogenous S1P levels.

Methods and Results Sub-lethally irradiated LDL-R−/− mice were transplanted with bone marrow deficient in sphingosine kinase 2 (SphK2), which led to the elevation of S1P concentrations in erythrocytes, plasma and HDL by approximately 1.5- to 2.0-fold in SphK2−/−/LDL-R−/− mice. Afterwards, mice were fed a Western diet for 14 weeks. Elevation of endogenous S1P significantly reduced atherosclerotic lesion formation by approximately half without affecting the plasma lipid profile. Furthermore, the macrophage content of atherosclerotic lesions and lipopolysaccharide-induced monocyte recruitment to the peritoneal cavity were reduced in SphK2−/−/LDL-R−/− mice. Studies using intra-vital microscopy revealed that endogenous S1P lowered leukocyte adhesion to capillary wall and decreased endothelial permeability to fluorescently labelled LDL. Moreover, SphK2−/−/LDL-R−/− mice displayed decreased levels of vascular cell adhesion molecule 1 in atherosclerotic lesions and in plasma. Studies in vitro demonstrated reduced monocyte adhesion and transport across an endothelial layer exposed to increasing S1P concentrations, murine plasma enriched in S1P or plasma obtained from SphK2-deficient animals. In addition, decreased permeability to fluorescence-labelled dextran beads or LDL was observed in S1P-treated endothelial cells.

Conclusion We conclude that raising endogenous S1P levels exerts anti-atherogenic effects in LDL-R−/− mice that are mediated by favourable modulation of endothelial function.

* Renata Feuerborn and Manuela Besser contributed equally to this study.


Supplementary Material