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Papers In Press, published online ahead of print February 1, 2008
J. Lipid Res., doi:10.1194/jlr.M700261-JLR200

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Journal of Lipid Research, Vol. 49, 324-331, February 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Myriocin slows the 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^1,*,**

^* Prince of Wales Medical Research Institute, Randwick NSW 2031, Australia
Centre for Vascular Research, University of New South Wales, Sydney NSW 2052, Australia
Heart Research Institute, Sydney NSW 2050, Australia
^** School of Medical Sciences, University of New South Wales, Sydney NSW 2052, Australia

The online version of this article (available at http://www.jlr.org) contains supplementary data.

Published, JLR Papers in Press, October 31, 2007.

¹ To whom correspondence should be addressed. e-mail: brett.garner{at}unsw.edu.au

The serine palmitoyl transferase inhibitor myriocin potently suppresses the development of atherosclerosis in apolipoprotein E (apoE) gene knockout (apoE^–/–) mice fed a high-fat diet. This is associated with reduced plasma sphingomyelin (SM) and glycosphingolipid levels. Furthermore, oral administration of myriocin decreases plasma cholesterol and triglyceride (TG) levels. Here, we aimed to determine whether myriocin could inhibit the progression (or stimulate the regression) of established atherosclerotic lesions and to 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 (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 celiac branch point) were measured. Although the inhibition of lesion progression was observed mainly 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 SM, cholesterol, and TG levels and increased hepatic and plasma apoA-I levels, indicating that the modulation of pathways associated with several classes of atherogenic lipids may be involved.

Supplementary key words atherosclerosis • sphingomyelin • glycosphingolipids • sphingolipid synthesis inhibition

Abbreviations: apoE, apolipoprotein E; GSL, glycosphingolipid; HF, high-fat chow; SM, sphingomyelin; TG, triglyceride

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