Fine Tuning Therapeutic Targeting of the Sphingolipid Biosynthetic Pathway to Treat Atherosclerosis

W.   S.   Kim; Charles   E.   Chalfant; Brett      Garner

Abstract

The accumulation of sphingolipids, including sphingomyelin and glycosphingolipids, in atherosclerotic lesions is well known. Plasma sphingomyelin concentration is correlated with atherosclerosis development and is an independent predictor of coronary artery disease. Similarly, plasma glycosphingolipid levels are increased in conditions associated with atherosclerosis risk. Recent studies have focused on understanding the mechanisms by which specific intermediates and end-products of the sphingolipid biosynthetic pathway, such as sphingomyelin, glycosphingolipids, ceramide and sphingosine-1-phosphate may modulate vascular biology and atherosclerosis. Here we focus on recent work indicating that pharmacological modulation of the sphingolipid biosynthetic pathway could offer a novel treatment for atherosclerosis or, at the very least, provide mechanistic insights concerning the eitiology of this disease which is the major cause of death in developed countries.

Keywords: Atherosclerosis, sphingomyelin, glycosphingolipids, ceramide kinase, ceramide-1-phosphate, myriocin, sphingolipid, inhibitors, ABCA-1