Submitted on March 26, 2008
Revised on May 5, 2008
Accepted on May 8, 2008
Reduction of plasma glycosphingolipid levels has no impact on atherosclerosis in apolipoprotein-E null mice
Elias N. Glaros, Woojin S. Kim, Kerry-Anne Rye, James A. Shayman, and Brett Garner
Cellular Lipidology Group, Prince of Wales Medical Research Institute, Sydney, NSW 2031
Corresponding Author: brett.garner{at}unsw.edu.au
Glycosphingolipids (GSLs) have been implicated as potential atherogenic lipids. Studies in apolipoprotein-E null (apoE-/-) mice indicate that exacerbated tissue GSL accumulation resulting from alpha-galactosidase deficiency promotes atherosclerosis whereas the serine palmitoyl transferase inhibitor myriocin (which reduces plasma and tissue levels of several sphingolipids including sphingomyelin, ceramide, sphingosine-1-phosphate and GSLs) inhibits atherosclerosis. It is not clear if GSL synthesis inhibition per se has an impact on atherosclerosis. In order to address this issue, apoE-/- mice maintained on a high fat diet were treated with a potent glucosylceramide synthesis inhibitor D-threo-1-ethylendioxyphenyl-2-palmitoyl amino-3-pyrrolidino-propanol (EtDO-P4) 10mg/kg/day for 94 days and lesion development was compared with mice that were treated with vehicle only. EtDO-P4 reduced plasma GSL concentration by approximately 50% but did not affect cholesterol or triglyceride levels. Assessment of atherosclerotic lesions at four different sites indicated that EtDO-P4 had no significant impact on lesion area. Thus despite the previously observed positive correlations between plasma and aortic GSL concentrations and the development of atherosclerosis, and the in vitro evidence implying that GSLs may be pro-atherogenic, our current data indicate that inhibition of GSL synthesis does not inhibit atherosclerosis in vivo.
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