Regulation of vascular proteoglycan synthesis by metabolic factors associated with diabetes

Background: Diabetes is associated with accelerated atherosclerosis, but the mechanisms responsible for this are not known. Proteoglycans have been shown to play a critical role in the initiation of atherosclerosis owing to their ability to bind and retain atherogenic lipoproteins in the artery wall. Proteoglycan structure and composition are altered in atherosclerotic lesions compared with adjacent normal regions of the artery wall, and this is exaggerated in diabetes. The purpose of this study was to determine if metabolic factors associated with diabetes lead to altered proteoglycan structure and composition. Methods: Vascular smooth muscle cells, endothelial cells, and macrophages were exposed to normal (5.6 mmol/L) or high (25 mmol/L) glucose levels, various insulin and free fatty acid levels, and the cytokines transforming growth factor p (TGF-β1) and platelet-derived growth factor, alone or in combination, and proteoglycan synthesis was determined. Results: Glucose concentrations, insulin, and free fatty acids did not alter proteoglycan synthesis, size, or relative distribution. The effect of TGF-β to increase biglycan and versican synthesis, increase sulfate incorporation, and increase the size of the secreted proteoglycans was not altered by the ambient glucose level in the culture medium, nor did high glucose increase levels of active TGF-β. Conclusion: Vascular proteoglycan synthesis is not affected by metabolic factors associated with diabetes. We suggest that elevated TGF-β levels in diabetes are responsible for the altered proteoglycan synthesis observed in diabetes.