SKI-II--a sphingosine kinase 1 inhibitor--exacerbates atherosclerosis in low-density lipoprotein receptor-deficient (LDL-R-/-) mice on high cholesterol diet

Atherosclerosis. 2015 May;240(1):212-5. doi: 10.1016/j.atherosclerosis.2015.03.020. Epub 2015 Mar 16.

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.

Keywords: Animal models of atherosclerosis; Hypercholesterolemia; Inflammation; Sphingosine 1-phosphate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta, Thoracic / drug effects*
  • Aorta, Thoracic / enzymology
  • Aorta, Thoracic / pathology
  • Aortic Diseases / chemically induced*
  • Aortic Diseases / enzymology
  • Aortic Diseases / genetics
  • Aortic Diseases / pathology
  • Atherosclerosis / chemically induced*
  • Atherosclerosis / enzymology
  • Atherosclerosis / genetics
  • Atherosclerosis / pathology
  • Biomarkers / blood
  • Cholesterol, Dietary*
  • Cholesterol, HDL / blood
  • Diet, Western*
  • Disease Models, Animal
  • Enzyme Inhibitors / toxicity*
  • Female
  • Hypercholesterolemia / complications
  • Hypercholesterolemia / genetics*
  • Intercellular Adhesion Molecule-1 / blood
  • Lysophospholipids / blood
  • Mice, Knockout
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Receptors, LDL / deficiency*
  • Receptors, LDL / genetics
  • Risk Factors
  • Sphingosine / analogs & derivatives
  • Sphingosine / blood
  • Thiazoles / toxicity*
  • Time Factors
  • Triglycerides / blood
  • Tumor Necrosis Factor-alpha / blood
  • Vascular Cell Adhesion Molecule-1 / blood

Substances

  • 4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol
  • Biomarkers
  • Cholesterol, Dietary
  • Cholesterol, HDL
  • Enzyme Inhibitors
  • Icam1 protein, mouse
  • Lysophospholipids
  • Receptors, LDL
  • Thiazoles
  • Triglycerides
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1
  • sphingosine 1-phosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Sphingosine