Renata Feuerborn1, Manuela Besser2, Francesco Potì3,4, Ralph Burkhardt5, Gabriele Weißen-Plenz1, Uta Ceglarek5, Manuela Simoni4, Richard L Proia6, Hendrik Freise2, Jerzy-Roch Nofer1. 1. Center for Laboratory Medicine, University Hospital Münster, University of Münster, Münster, Germany. 2. Department of Anaesthesiology and Intensive Medicine, University Hospital Münster, University of Münster, Münster, Germany. 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. 5. Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, University of Leipzig, Leipzig, Germany. 6. Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States.
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. Georg Thieme Verlag KG Stuttgart · New York.
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. Georg Thieme Verlag KG Stuttgart · New York.
Authors: Srividya Velagapudi; Lucia Rohrer; Francesco Poti; Jerzy-Roch Nofer; Arnold von Eckardstein; Renate Feuerborn; Damir Perisa; Dongdong Wang; Grigorios Panteloglou; Anton Potapenko; Mustafa Yalcinkaya; Andreas J Hülsmeier; Bettina Hesse; Alexander Lukasz; Mingxia Liu; John S Parks; Christina Christoffersen; Markus Stoffel; Manuela Simoni Journal: Arterioscler Thromb Vasc Biol Date: 2021-08-19 Impact factor: 10.514
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