Abstract 215: Glycosphingolipids Contribute to Pro-atherogenic Pathways in the Pathogenesis of Hyperglycemia-induced Atherosclerosis

Abstract

Three out of every four people with diabetes will die of cardiovascular disease. However, the molecular mechanisms by which diabetes promotes atherosclerosis are not clear. In this study, comprehensive metabolomic techniques were used to investigate the molecular mechanisms by which hyperglycemia promotes accelerated atherogenesis in three distinct disease mouse models. Normoglycemic apolipoprotein E-deficient mice served as the atherosclerotic control. Hyperglycemia was induced by multiple low-dose streptozotocin injections or by introducing a point mutation in one copy of the insulin-2 gene. Glucosamine-supplemented mice, which experience accelerated atherosclerosis to a similar extent as the hyperglycemia-induced models, without alterations in the levels of glucose or insulin, were also included in the analysis. Mice with accelerated atherosclerosis showed distinct metabolomic profiles compared to the controls. We detected 6369 metabolite features in the plasma of each mouse. Second-order analysis of pair comparisons between each disease model and the control resulted in 62 commonly altered features (p<0.05). Identification of shared metabolites revealed alterations in glycerophospholipid and sphingolipid metabolisms, and pro-atherogenic processes including inflammation and oxidative stress. Post-multivariate and pathway analyses indicated glycosphingolipid metabolism is the most significantly altered pathway. Glycosphingolipid metabolites induced oxidative stress and inflammation in cultured human vascular cells including macrophages, endothelial and smooth muscle cells. Treatment with a known antioxidant, α-tocopherol, reduced oxidative stress and inflammation induced by glycosphingolipids. Our findings suggest that the glycosphingolipid pathway contributes to pro-atherogenic pathways in the pathogenesis of hyperglycemia-induced atherosclerosis, making it a potential therapeutic target to block or slow atherogenesis in diabetic patients.