Francesco Potì1, Uta Ceglarek2, Ralph Burkhardt2, Manuela Simoni1, Jerzy-Roch Nofer3. 1. Department of Biomedical, Metabolic and Neural Sciences - Endocrinology Section, University of Modena and Reggio Emilia, Italy. 2. Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany. 3. Department of Biomedical, Metabolic and Neural Sciences - Endocrinology Section, University of Modena and Reggio Emilia, Italy; Center for Laboratory Medicine, University Hospital Münster, Germany. Electronic address: nofer@uni-muenster.de.
Abstract
BACKGROUND: Sphingosine 1-phosphate (S1P) is a lysosphingolipid associated with high-density lipoproteins (HDL) that contributes to their anti-atherogenic potential. We investigated whether a reduction in S1P plasma levels affects atherosclerosis in low-density lipoprotein receptor deficient (LDL-R-/-) mice. METHODS AND RESULTS: LDL-R-/- mice on Western diet containing low (0.25% w/w) or high (1.25% w/w) cholesterol were treated for 16 weeks with SKI-II, a sphingosine kinase 1 inhibitor that significantly reduced plasma S1P levels. SKI-II treatment increased atherosclerotic lesions in the thoracic aorta in mice on high but not low cholesterol diet. This compound did not affect body weight, blood cell counts and plasma total and HDL cholesterol, but decreased triglycerides. In addition, mice on high cholesterol diet receiving SKI-II showed elevated levels of tumor necrosis factor-α and endothelial adhesion molecules (sICAM-1, sVCAM-1). CONCLUSION: Prolonged lowering of plasma S1P produces pro-atherogenic effects in LDL-R-/- mice that are evident under condition of pronounced hypercholesterolemia.
BACKGROUND: Sphingosine 1-phosphate (S1P) is a lysosphingolipid associated with high-density lipoproteins (HDL) that contributes to their anti-atherogenic potential. We investigated whether a reduction in S1P plasma levels affects atherosclerosis in low-density lipoprotein receptor deficient (LDL-R-/-) mice. METHODS AND RESULTS: LDL-R-/- mice on Western diet containing low (0.25% w/w) or high (1.25% w/w) cholesterol were treated for 16 weeks with SKI-II, a sphingosine kinase 1 inhibitor that significantly reduced plasma S1P levels. SKI-II treatment increased atherosclerotic lesions in the thoracic aorta in mice on high but not low cholesterol diet. This compound did not affect body weight, blood cell counts and plasma total and HDL cholesterol, but decreased triglycerides. In addition, mice on high cholesterol diet receiving SKI-II showed elevated levels of tumor necrosis factor-α and endothelial adhesion molecules (sICAM-1, sVCAM-1). CONCLUSION: Prolonged lowering of plasma S1P produces pro-atherogenic effects in LDL-R-/- mice that are evident under condition of pronounced hypercholesterolemia.