Myriocin slows progression of established atherosclerotic lesions in apolipoprotein-E gene knockout mice

Elias N. Glaros, Woojin S. Kim, Carmel M. Quinn, Wendy Jessup, Kerry-Anne Rye, and Brett Garner

Cellular Lipidology Group, Prince of Wales Medical Research Institute, Sydney, NSW 2031

Corresponding Author: brett.garner{at}unsw.edu.au

The serine palmitoyl transferase inhibitor myriocin potently suppresses the development of atherosclerosis in apoE gene knockout (apoE-/-) mice fed a high fat diet. This is associated with reduced plasma sphingomyelin and glycosphingolipid levels. Furthermore, oral administration of myriocin lowers plasma cholesterol and triglyceride levels. Here we aimed to determine if myriocin could inhibit the progression (or stimulate regression) of established atherosclerotic lesions and examine potential changes in hepatic and plasma lipid concentrations. Adult apoE-/- mice were fed a high fat diet for 30 days and lesion formation was histologically confirmed. Replicate groups of mice were then transferred to either regular chow or chow containing myriocin (dose 0.3 mg/kg/day) and maintained for a further 60 days. Myriocin significantly inhibited the progression of established atherosclerosis when combined lesion areas (aortic sinus, arch and coeliac branch point) were measured. While inhibition of lesion progression was mainly observed in the distal regions of the aorta, regression of lesion size was not detected. The inhibition of lesion progression was associated with reductions in hepatic and plasma sphingomyelin, cholesterol and triglyceride levels and increased hepatic and plasma apoA-I levels indicating that modulation of pathways associated with several classes of atherogenic lipid may be involved.

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