Chronic Vascular Inflammation in Patients With Type 2 Diabetes

Abstract

OBJECTIVE -Chronic vascular inflammation may play a role in the development of macrovascular complications in diabetic patients. In this study, we examine the association of endothelial expression of two inflammatory mediators, receptor for advanced glycation end product (RAGE) and monocyte chemoattractant protein-1 (MCP-1), with type 2 diabetes using novel endothelial biopsy and RT-PCR techniques.RESEARCH DESIGN AND METHODS -Endothelial samples are obtained from the aorta of 12 patients with type 2 diabetes and 23 control subjects who underwent cardiac catheterization for chest pain syndrome or heart transplant follow-up. Endothelial cells are purified using magnetic beads with adsorbed CD146 antibody and subjected to RT-PCR analysis of RAGE and MCP-1 transcripts. The association of RAGE and MCP-1 expression with type 2 diabetes is assessed with 2 test and confirmed with in vitro experiments on human aorta endothelial cells.RESULTS -RT-PCR reveals gene expression patterns in patient-derived endothelial cells. Strong associations are observed between induction of RAGE mRNA and diabetes (P Ͻ 0.01) and between induction of RAGE and MCP-1 transcripts (P Ͻ 0.05). Treatment of cultured human aortic endothelial cells with S100b induces the expression of MCP-1 and RAGE transcripts.CONCLUSIONS -Endothelial cells can be harvested during cardiac catheterization and can be characterized with respect to molecular phenotypes under the influence of both genetic and environmental factors. Induction of RAGE and MCP-1 transcripts in patients with diabetes supports a role of chronic vascular inflammation in macrovascular complications. Diabetes Care 28:379 -384, 2005E xperimental data have shown that hyperglycemia may induce a chronic inflammatory state in the vessel wall, thus accelerating the development of macrovascular complications (1-4). Hyperglycemia and oxidant stress promote nonenzymatic glycoxidation of proteins and lipids. The final products of these reactions, termed advanced glycation end products (AGEs), have both direct and indirect effects. Direct activities of AGEs include the capacity to alter vessel wall architecture through formation of intermolecular crosslinks and trapping of plasma components, reducing elasticity. AGE-mediated generation of low levels of reactive oxygen species can result in quenching of the endogenous vasorelaxant nitric oxide. By interacting with the receptor for AGE (RAGE), AGEs magnify their biologic effects considerably by recruiting cellular elements. RAGE is a member of the immunoglobulin superfamily of cell surface molecules with a ligand repertoire, including AGEs (5,6), S100/calgranulins (7), amyloid-␤ peptide (8), and amphoterin (9). Engagement of RAGE triggers signaling cascades in which activation of NADPH oxidase recruits multiple downstream pathways, including p21 ras , the mitogen-activated protein kinases, nuclear translocation of nuclear factor-kB, phosphatidylinositol 3-kinase, cdc42/rac, and the Jak/stat pathway (7,10,11). Two general outcomes of RAGE-mediated cellular a...

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