Abstract 550: Alteration of Glycolysis Metabolite Levels and Impaired Hypoxic Response in Diabetic Atherosclerosis

Abstract

Objective: Diabetes mellitus accelerates atherosclerosis that causes most cardiovascular events. Several metabolic pathways are considered to contribute to the development of atherosclerosis, but comprehensive metabolic alterations to atherosclerotic arterial cells remain unknown. The present study investigated metabolic status and their relationship to vascular histopathological changes in the atherosclerotic arteries of rabbits with alloxan-induced diabetes. Approach and Results: Diabetic atherosclerosis was induced in rabbits ilio-femoral arteries by injecting alloxan (100 mg/kg), injuring the arteries using a balloon, and feeding with a 0.5% cholesterol diet. Plaque burden, macrophage content, and hypoxic areas were more prevalent in arteries with diabetic, than non-diabetic atherosclerosis. Metabolomic analyses highlighted 12 metabolites that were significantly altered between diabetic and non-diabetic atherosclerosis. A half of them were associated with glycolysis metabolites, and their levels were decreased in diabetic atherosclerosis. The uptake of glucose evaluated as 18 F-fluorodeoxyglucose in atherosclerotic lesions increased according to increased macrophage content or hypoxic areas in non-diabetic, but not diabetic rabbits. Despite profound hypoxic areas, the nuclear localization of hypoxia-inducible factor-1α decreased and the number of apoptotic cells increased in diabetic atherosclerotic lesions. Conclusions: Altered glycolysis metabolism and an impaired response to hypoxia in atherosclerotic lesions under conditions of insulin-dependent diabetes might be involved in the development of diabetic atherosclerosis.