Inhibition of glycosphingolipid synthesis ameliorates atherosclerosis and arterial stiffness in Apo E‐/‐ mice and rabbits fed a high fat and cholesterol diet (607.11)

Abstract

Objective ‐‐ Glycosphingolipids are integral components of the cell membrane and have been shown to serve as messengers, transducing growth factor initiated phenotypes. Here we have examined whether inhibition of glycosphingolipid synthesis could ameliorate atherosclerosis and arterial stiffness in transgenic mice and in rabbits.Methods and Results ‐‐ Apolipoprotein E‐/‐ (apoE‐/‐) mice (12 weeks of age, n = 6) were fed regular chow or a western diet (1.25% cholesterol, 2% fat). Mice were fed 5mg/kg (mpk) or 10 mpk of an inhibitor of glycosphingolipid synthesis inhibitor D‐threo‐1‐phenyl‐2‐decanoylamino‐3‐morpholino‐1‐propanol (D‐PDMP) solubilized in vehicle (5% Tween‐80 in PBS) and the placebo group received vehicle only. At 20 weeks and 36 weeks of age, serial echocardiography was performed without sedation to measure aortic pulse wave velocity (PWV). Feeding mice a western diet markedly increased aortic PWV, aortic intima medial thickening (IMT), oxidized LDL, Ca2+ deposits, and glucosyl‐ and lactosylceramide synthase activity. These were dose‐dependently decreased by feeding D‐PDMP. In liver, D‐PDMP decreased cholesterol and triglyceride levels by raising the expression of SREBP‐1, LDL‐r, HMGCo‐A reductase, and cholesterol efflux genes (e.g., ABCG5, ABCG8). D‐PDMP affected VLDL catabolism by increasing the gene expression for LPL and VLDLr. Rabbits fed a western diet for 90 days had extensive atherosclerosis accompanied by a 17.5‐fold increase in total cholesterol levels and a 3‐fold increase in lactosylceramide levels. This was completely reversed by feeding D‐PDMP.Conclusions ‐‐ Inhibition of glycosphingolipid synthesis ameliorates atherosclerosis and arterial stiffness in ApoE‐/‐ mice and rabbits. Thus, inhibition of glycosphingolipid synthesis may be a novel approach to treating atherosclerosis and arterial stiffness.Grant Funding Source: Supported by P01HL107153