Potential role of advanced glycosylation end products in promoting restenosis in diabetes and renal failure

Abstract 

Diabetes and renal failure have been associated with extremly high restenosis rates following successful angioplasty, resulting in increased morbidity and mortality. Advanced glycosylation end products (AGEs) accumulate in vascular tissues with aging and at an accelerated rate in diabetes and renal failure. AGEs are particularly abundant at sites of atherosclerotic lesions. AGEs interact with specific receptors (RAGE) present on all cells relevant to the restenosis process including inflammatory cells and smooth muscle cells. AGEs–RAGE interaction in vessel wall may lead to inflammation, smooth muscle cell proliferation, and extracellular matrix production, culminating in exaggerated intimal hyperplasia and restenosis. Following arterial injury, the interaction of AGEs with monocytes expressing RAGE can promote migration of inflammatory cells into the lesion and subsequent release of growth factors and cytokines. Binding of AGEs–RAGE on smooth muscle cells increases chemotactic migration and cellular proliferation. AGEs trigger the generation of reactive oxygen species, and upregulate the multifunctional transcription factor NF-κB. Finally, AGEs can augment extracellular matrix production by upregulating transforming growth factor-β. Thus, accumulation of AGEs in vessel wall provides a common mechanism for the high restenosis rates of patients with diabetes and renal failure.