Sugar-Coating the Road to Atherosclerosis

Abstract

Diabetes promotes the development of atherosclerosis, increasing the risk of such serious complications as myocardial infarctions, stroke, and amputation. Indeed, most people with diabetes die of conditions associated with atherosclerosis. Hyperglycemia leads to an increase in the abundance of thrombospondin-1 (TSP-1), which has pro-atherogenic effects, providing one potential link between diabetes and the enhanced development of atherosclerotic lesions. Raman et al . exposed cultured human aortic smooth muscle cells (HASMC) to glucose, glucose analogs that participate in distinct segments of glucose metabolism, and other sugars to implicate protein glycosylation mediated by way of the hexosamine pathway in the increase in TSP-1 mRNA abundance elicited by high glucose concentrations. Pharmacological analysis further supported a role for the hexosamine pathway and protein glycosylation in this response, as did experiments involving overexpression of GFAT (glutamine:fructose 6-phosphate amidotransferase, the rate-limiting enzyme in the hexosamine pathway). Glucose did not affect TSP-1 mRNA stability but enhanced its transcription, as well as that of a reporter gene containing the TSP-1 promoter. Glucose also increased the glycosylation of proteins in the nucleus. Glucose and analogs that enhanced TSP-1 production stimulated the proliferation of HASMC, an effect that was mimicked by exposure of cells to TSP-1 and was blocked by pharmacological inhibition of GFAT or of glycosylation, and by siRNA or antibodies directed against TSP-1. Thus, the authors conclude that the hexosamine pathway and the glycosylation of nuclear proteins may contribute to the development of atherosclerotic lesions in response to high glucose. P. Raman, I. Krukovets, T. E. Marinic, P. Bornstein, O. I. Stenina, Glycosylation mediates up-regulation of a potent antiangiogenic and proatherogenic protein, thrombospondin-1, by glucose in vascular smooth muscle cells. J. Biol. Chem. 282 , 5704-5714 (2007). [Abstract] [Full Text]