Dicarbonyl stress and atherosclerosis: is it all RAGE?

Abstract

Atherosclerotic vascular disease is a major cause of cardiovascular (CV) morbidity and mortality and a significant driver of health care costs in patients with diabetes. Systemic abnormalities, including dyslipidemia, insulin resistance, hyperinsulinemia, hyperglycemia, oxidative stress, accentuated renin-angiotensin system, and tissue inflammation, have been proposed to play a role in mediating accelerated atherosclerosis in diabetes (1). Hyperglycemia not only predicts CV disease risk in individuals without known CV disease or diabetes (2), but atherosclerosis is also quite prevalent in prediabetes (3). Although difficult to achieve, near-normal glycemic control is not typically associated with further reduction in macrovascular events in patients with type 2 diabetes (4). Consequently, elucidating mechanisms by which hyperglycemia affects atherosclerosis is necessary to identify novel therapeutic targets. Increased mitochondrial reactive oxygen species (ROS) has been identified as a common upstream event that mediates the atherogenic effects of hyperglycemia (5). ROS increases the formation of advanced glycation end products (AGEs), augments the expression of the receptor for AGEs (RAGE) and its ligands, activates protein kinase C (PKC) isoforms (primarily PKCβ isoform), and accentuates flux through the hexosamine and polyol pathways (5). Among these, the ligand-RAGE axis appears to play a major role in vascular dysfunction in diabetes. AGEs, S100/calgranulins, and high-mobility group box 1 are principal endogenous ligands for RAGE (6). Persistent activation of RAGE promotes atherosclerosis by activating a diverse array of intracellular signaling pathways that stimulate expression of cytokines, cellular adhesion molecules, growth factors, ROS, and vascular matrix metalloproteinases (6). Diabetes-induced atherosclerosis …