title: SKI-II--a sphingosine kinase 1 inhibitor--exacerbates atherosclerosis in low-density lipoprotein receptor-deficient (LDL-R-/-) mice on high cholesterol diet.
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.
  
  
  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).
  
  
  CONCLUSIONS
  Prolonged lowering of plasma S1P produces pro-atherogenic effects in LDL-R-/- mice that are evident under condition of pronounced hypercholesterolemia.
authors: Department of Biomedical, Metabolic and Neural Sciences - Endocrinology Section, University of Modena and Reggio Emilia, Italy.
authors: Francesco
authors: F
authors: Potì
authors: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.
authors: Uta
authors: U
authors: Ceglarek
authors: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.
authors: Ralph
authors: R
authors: Burkhardt
authors: Department of Biomedical, Metabolic and Neural Sciences - Endocrinology Section, University of Modena and Reggio Emilia, Italy.
authors: Manuela
authors: M
authors: Simoni
authors: 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.
authors: Jerzy-Roch
authors: JR
authors: Nofer
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D001018:Aortic Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D050197:Atherosclerosis / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D015415:Biomarkers / Q000097:blood; D002791:Cholesterol, Dietary; D008076:Cholesterol, HDL / Q000097:blood; D066273:Diet, Western; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D006937:Hypercholesterolemia / Q000150:complications / Q000235:genetics*; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D008246:Lysophospholipids / Q000097:blood; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D012307:Risk Factors; D013110:Sphingosine / Q000031:analogs & derivatives / Q000097:blood; D013844:Thiazoles / Q000633:toxicity*; D013997:Time Factors; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood; D000099157:Sphingosine Kinase
chemical_list: D015415:Biomarkers; D002791:Cholesterol, Dietary; D008076:Cholesterol, HDL; D004791:Enzyme Inhibitors; D018799:Intercellular Adhesion Molecule-1; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D011973:Receptors, LDL; D013110:Sphingosine; D013844:Thiazoles; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D000099157:Sphingosine Kinase; C525025:4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol; C090509:Icam1 protein, mouse; C060506:sphingosine 1-phosphate
keywords: Animal models of atherosclerosis; Hypercholesterolemia; Inflammation; Sphingosine 1-phosphate