Cardiovascular disease is the leading cause of death in diabetes mellitus patients. Medial calcification in diabetic patients is a strong predictor of cardiovascular mortality independent of other factors. The role of glucose metabolism in vascular smooth muscle (VSMC) osteochondrogenic differentiation has recently been highlighted and is an area of growing interest. Calcifying VSMC have increased glucose uptake and glycolysis. To further investigate the role of metabolism in vascular calcification we cultured primary mouse aortic smooth muscle cells (MASMC) in high phosphate (3 mM) medium to induce calcification, calcium content was determined by a modified O-Cresolphtalein method and normalised to total protein. Inhibiting glycolysis using 2-deoxyglucose (10 µM) decreased high phosphate induced calcification by ~30% (p < 0.05). In contrast, Fasentin (60 µM) a specific inhibitor of the predominant glucose transporter in VASMC (Glut1) induced a ~ 72% (p < 0. 01) increase in high phosphate induced calcification. Glycolysis produces pyruvate which is either converted to acytel-CoA by the pyruvate dehydrogenase complex or lactate by lactate dehydrogenase. Sodium dicholoroacetate (20 mM), a general pyruvate dehydrogenase kinase inhibitor, decreased high phosphate induced calcification by ~40% (p < 0.01). Sodium oxamate (60 mM), a pyruvate analogue and lactate dehydrogenase inhibitor, decreased high phosphate induced calcification by ~300% (p < 0.05). Together these data suggest glycolysis plays a role in smooth muscle calcification and that lactate production is necessary for this process. Elevated circulating lactate is a common occurrence in diabetes patients and these finding suggest it may contribute to the increased prevalence of vascular calcification in this population.
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