RAGE DEFICIENCY ATTENUATES THE DEVELOPMENT OF ATHEROSCLEROSIS IN DIABETES

Abstract

Objective: Activation of the Receptor for Advanced Glycation End-products (RAGE) in diabetic vasculature is considered to be a key mediator of atherogenesis. This study examines the effects of deletion of RAGE on the development of atherosclerosis in the diabetic apoE^−/− model of accelerated atherosclerosis.

Research Design and Methods: ApoE^−/− and RAGE^−/−/apoE^−/− double knock-out (KO) mice were rendered diabetic with streptozotozin and followed for 20 weeks, at which time plaque accumulation was assessed by en face analysis.

Results: While diabetic apoE^−/− mice showed increased plaque accumulation (14.9±1.7%), diabetic RAGE^−/−/apoE^−/− mice had significantly reduced atherosclerotic plaque area (4.9±0.4%) to levels not significantly different to control apoE-/- mice (4.3±0.4%). These beneficial effects on the vasculature were associated with attenuation of leucocyte recruitment, decreased expression of proinflammatory mediators including the NF-kB subunit p65, VCAM-1, MCP-1, reduced oxidative stress, as reflected by staining for nitrotyrosine and reduced expression of various NADPH oxidase subunits, gp91phox, p47phox and rac-1. Both RAGE and RAGE-ligands, including S100A8/9, HMGB1 and the AGE, carboxymethyllysine (CML) were increased in plaques from diabetic apoE^−/− mice. Furthermore, the accumulation of AGEs and other ligands to RAGE was reduced in diabetic RAGE^−/−/apoE^−/− mice.

Conclusions: This study provides evidence for RAGE playing a central role in the development of accelerated atherosclerosis associated with diabetes. These findings emphasize the potential utility of strategies targeting RAGE activation in the prevention and treatment of diabetic macrovascular complications.