sphingosine-1-phosphate and Aortic-Diseases

Chronic kidney disease is characterized by uremia and causes premature death, partly due to accelerated atherosclerosis. Apolipoprotein (apo) M is a plasma carrier protein for the lipid sphingosine-1-phosphate (S1P). The Apom-S1P complex associates with HDL, and may contribute to its anti-atherosclerotic effects. The role of Apom/S1P in atherosclerosis is presently controversial and has not been explored in a uremic setting. We aimed to explore whether plasma concentrations of Apom/S1P are altered by uremia and whether Apom overexpression or deficiency affects classical and uremic atherosclerosis.. Mild to moderate uremia was induced by subtotal nephrectomy (NX) in 86-92 Apoe-deficient mice that were either Apom-wild type, Apom-deficient, or overexpressed Apom (∼10 fold). The effects of uremia on plasma Apom/S1P and atherosclerosis were evaluated and compared to non-nephrectomized controls.. Uremia increased plasma Apom by ∼25%, but not S1P. Plasma S1P was elevated by ∼300% in mice overexpressing Apom, and decreased by ∼25% in Apom-deficient mice. Apom overexpression augmented aortic root atherosclerosis and plasma cholesterol. In contrast, aortic arch atherosclerosis was unaffected by the Apom genotype. There was no effect of Apom-deficiency or Apom overexpression on uremic atherosclerosis.. This study highlights the complexity of Apom/S1P in atherosclerosis and challenges the notion that the Apom/S1P complex is anti-atherogenic, at least in Apoe-deficient mice.

Topics: Animals; Aortic Diseases; Apolipoproteins M; Atherosclerosis; Cholesterol; Disease Models, Animal; Female; Genetic Predisposition to Disease; Humans; Lysophospholipids; Mice, Inbred C57BL; Mice, Knockout, ApoE; Nephrectomy; Phenotype; Plaque, Atherosclerotic; Sphingosine; Uremia

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.. 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).. Prolonged lowering of plasma S1P produces pro-atherogenic effects in LDL-R-/- mice that are evident under condition of pronounced hypercholesterolemia.

Topics: Animals; Aorta, Thoracic; Aortic Diseases; Atherosclerosis; Biomarkers; Cholesterol, Dietary; Cholesterol, HDL; Diet, Western; Disease Models, Animal; Enzyme Inhibitors; Female; Hypercholesterolemia; Intercellular Adhesion Molecule-1; Lysophospholipids; Mice, Knockout; Phosphotransferases (Alcohol Group Acceptor); Receptors, LDL; Risk Factors; Sphingosine; Thiazoles; Time Factors; Triglycerides; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1