Role of Ligands of Receptor for Advanced Glycation End Products (RAGE) in Peripheral Artery Disease

Atherosclerotic cardiovascular disease, including peripheral artery disease (PAD), is more common and severe in diabetic patients compared with nondiabetic individuals. Indeed, diabetes is associated with the increased risk of limb amputation and all-cause mortality in patients with symptomatic PAD. Proteins and lipids are nonenzymatically modified by sugars, resulting in the formation and accumulation of advanced glycation end products (AGEs), whose process is accelerated under diabetic conditions, especially patients with a long duration of diabetes. Accumulating evidence shows that nonenzymatic modification by sugars alters the structural integrity of collagens and lipoproteins in large vessels, thereby being involved in vascular stiffness and atherosclerotic plaque instability. Furthermore, engagement of receptor for AGEs (RAGE) with its ligands, such as AGEs, high mobility group box 1, and S100A proteins evokes inflammatory and thrombotic reactions, thus playing a central role in the development and progression of atherosclerotic cardiovascular disease. In this article, we review the pathophysiological role of RAGE ligands in PAD and discuss the clinical utility of measurement of plasma, serum, or tissue RAGE ligands for assessment of the severity and prognosis of PAD. This review suggests that RAGE ligands may be a novel biomarker and also a therapeutic target of PAD, especially in patients with diabetes.