Cardiovascular complications play a major role in determining the morbidity and mortality of diabetes mellitus. Enhanced monocyte adherence to the vascular endothelium is thought to be an early step in the development of atherosclerosis. Preliminary studies in the applicant's laboratory indicate that monocyte adherence and the expression of an important chemokine (monocyte chemotactic protein-1 [MCP-1]) is increased in the vascular wall of diabetic animals. In vitro studies indicate that hyperglycemia stimulates the expression of MCP-1 in VSMC at the level of mRNA abundance, and that this effect of glucose may involve interactions between signaling and metabolic pathways. The applicant proposes studies to: 1) determine whether glucose regulates MCP-1 expression at the level of gene transcription in cultured VSMC and in vivo; 2) delineate the roles of superoxide anion and PKC in the stimulation of MCP-1 expression by high glucose; 3) examine the role of these pathways in the regulation of MCP-1 expression in vivo. Together, it is hoped that these studies will provide new information regarding the role of a potentially novel mechanism by which hyperglycemia may contribute to the pathogenesis of macrovascular disease.
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