Accumulation of glycosphingolipids in human atherosclerotic plaque and unaffected aorta tissues

Abstract

We have measured the levels of glycosphingolipids and the activity of glycosphingolipid glycosyltransferases in human aortic intima and media from patients who died of atherosclerosis. The effects of lactosylceramide (LacCer) and glucosylceramide (GlcCer) from plaque intima on smooth muscle cell proliferation were assessed. When the GlcCer data was expressed as (micrograms GlcCer/mg cholesterol and/mg total phospholipid, a 28-fold and 7-fold increase in plaque intima compared to normal intima was observed. Similarly, the level of LacCer was elevated 5-fold and 4-fold, respectively, compared to unaffected intima. The activity of UDP-GlcCer: ceramide beta 1-->4 glucosyltransferase (GlcT-1) was similar in unaffected tissue, fatty streaks, and plaques. However, the activity of UDP-galactose: GlcCer, beta 1-->4 galactosyltransferase (GalT-2) activity was moderately higher in plaque than in unaffected tissue. LacCer, but not GlcCer derived from plaque intima exerted a approximately 2.8-fold increase in the proliferation of human aortic smooth muscle cells grown in tissue culture compared to control presumably due to a marked increase in LacCer molecular species containing C16:0, C22:1, and C24:0 fatty acids in plaque intima compared to control. In sum, our findings provide an interesting and novel pathogenic mechanism of lactosylceramide mediated plaque formation via stimulation of aortic smooth muscle cell proliferation.

Endotoxin and Cytokines Increase Hepatic Sphingolipid Biosynthesis and Produce Lipoproteins Enriched in Ceramides and Sphingomyelin

“…48,49 More recently, it was reported that there is marked accumulation of glucosylceramide and lactosylceramide in human atherosclerotic plaques. 50,51 The activity of SPT, the rate-limiting enzyme in sphingolipid synthesis, is also increased in rabbit aorta during experimental atherogenesis. 52 Taken together, these findings support the concept that enhanced sphingolipid synthesis leading to the enrichment of lipoproteins with ceramide, glucosylceramide, and sphingomyelin may be an important determinant of their atherogenic potential.…”

Sphingolipids in Atherosclerosis and Vascular Biology

“…11 Increased activity of GalT-2 and increased levels of LacCer in familial hypercholesterolemia and in atherosclerosis has been reported. 12,13 The levels of other GSLs in fatty streaks and plaques have also been reported. 13,14 Nevertheless, up to now, a human metabolic disease due to the abnormal biosynthesis of GSL has not been shown.…”

“…12,13 The levels of other GSLs in fatty streaks and plaques have also been reported. 13,14 Nevertheless, up to now, a human metabolic disease due to the abnormal biosynthesis of GSL has not been shown. In fact, the biochemical basis of several inherited sphingoglycolipidoses is due to the inability of these patients to hydrolyze various GSLs and sphingomyelin.…”

Disialoganglioside (GD3) Synthase Gene Expression Suppresses Vascular Smooth Muscle Cell Responses via the Inhibition of ERK1/2 Phosphorylation, Cell Cycle Progression, and Matrix Metalloproteinase-9 Expression

“…DISCUSSION A number of reports have appeared on the modulation of cell growth and differentiation by glycosphingolipids (23-25). In the past few years, several groups have reported an accumulation of gangliosides in atherosclerosis vessels (35,36). Many of these studies were performed by adding exogenous glycolipids into the culture medium of cell lines under investigation.…”

“…On the other hand, the overexpression of GD3 synthase led to apoptosis in human leukemic cells (34). In the past few years, increased levels of GD3 have been found to be associated with proliferative disease, such as atherosclerosis (35,36). A recent study suggested that exogenously supplied GD3 has a dual role in modulating VSMC proliferation and apoptosis (37).…”