Elevating Endogenous Sphingosine-1-Phosphate (S1P) Levels Improves Endothelial Function and Ameliorates Atherosclerosis in Low Density Lipoprotein Receptor-Deficient (LDL-R-/-) Mice
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Elevating Endogenous Sphingosine-1-Phosphate (S1P) Levels Improves Endothelial Function and Ameliorates Atherosclerosis in Low Density Lipoprotein Receptor-Deficient (LDL-R-/-) Mice. / Feuerborn, Renata; Besser, Manuela; Potì, Francesco; Burkhardt, Ralph; Weißen-Plenz, Gabriele; Ceglarek, Uta; Simoni, Manuela; Proia, Richard L; Freise, Hendrik; Nofer, Jerzy-Roch.
in: THROMB HAEMOSTASIS, Jahrgang 118, Nr. 8, 08.2018, S. 1470-1480.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Elevating Endogenous Sphingosine-1-Phosphate (S1P) Levels Improves Endothelial Function and Ameliorates Atherosclerosis in Low Density Lipoprotein Receptor-Deficient (LDL-R-/-) Mice
AU - Feuerborn, Renata
AU - Besser, Manuela
AU - Potì, Francesco
AU - Burkhardt, Ralph
AU - Weißen-Plenz, Gabriele
AU - Ceglarek, Uta
AU - Simoni, Manuela
AU - Proia, Richard L
AU - Freise, Hendrik
AU - Nofer, Jerzy-Roch
N1 - Georg Thieme Verlag KG Stuttgart · New York.
PY - 2018/8
Y1 - 2018/8
N2 - 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.
AB - 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.
KW - Animals
KW - Aorta/metabolism
KW - Aortic Diseases/blood
KW - Atherosclerosis/blood
KW - Capillary Permeability
KW - Coculture Techniques
KW - Diet, Western
KW - Disease Models, Animal
KW - Endothelial Cells/metabolism
KW - Genetic Predisposition to Disease
KW - Humans
KW - Leukocyte Rolling
KW - Lipoproteins, HDL/blood
KW - Lysophospholipids/blood
KW - Macrophages/metabolism
KW - Mice, Knockout
KW - Monocytes/metabolism
KW - Phenotype
KW - Phosphotransferases (Alcohol Group Acceptor)/deficiency
KW - Plaque, Atherosclerotic
KW - Receptors, LDL/deficiency
KW - Signal Transduction
KW - Sphingosine/analogs & derivatives
KW - U937 Cells
KW - Up-Regulation
KW - Vascular Cell Adhesion Molecule-1/blood
U2 - 10.1055/s-0038-1666870
DO - 10.1055/s-0038-1666870
M3 - SCORING: Journal article
C2 - 30060257
VL - 118
SP - 1470
EP - 1480
JO - THROMB HAEMOSTASIS
JF - THROMB HAEMOSTASIS
SN - 0340-6245
IS - 8
ER -
