Background and aims: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
Keywords: Apolipoproteins; Apom; Chronic kidney disease; HDL; Inflammation; Mediation; Nephrectomy; Nitric oxide; Sphingosine-1-phosphate; Uremia.
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