Dicarbonyl Stress and Atherosclerosis: Is It All RAGE?

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 PKCb 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 and vascular dysfunction are attenuated in RAGE-null mice confirming the pivotal role played by the ligandRAGE axis (7,8). AGEs are formed by rearrangement of Amadori products or as a result of reactions between dicarbonyls and amino acid residues (lysine, arginine, and cysteine) (9). Methylglyoxal (MG) is a highly reactive a-dicarbonyl and a major precursor of cellular and circulating AGEs (9). MG is primarily derived from triose phosphate intermediates formed during glycolysis (9). In humans, plasma/tissue MG concentrations are ;1–5 mmol/L (10). More than 99% of cellular MG is metabolized by glyoxalase 1 (GLO1), GLO2, and reduced glutathione to D-lactate (11). Glycation of arginine residues by MG results in the formation of hydroimidazolones (MG-H1, MG-H2, and MG-H3) and that of lysine leads to N-(carboxymethyl) lysine (CML) and N-(carboxyethyl) lysine (CEL) (12). MG-H1 is the most prevalent MG-derived AGE with plasma concentration of ;17 mmol/L in healthy individuals (12). Unlike CML/CELs, MG-Hs have a higher binding affinity to RAGE (KD, ;40 nmol/L vs. 100 mmol/L) (13). Hyperglycemia and diabetes are associated with increased formation and decreased metabolism of MG (14,15). Thus, MG-Hs are capable of sustained activation of RAGE in the vasculature and circulating inflammatory cells (Figure 1). Overexpression of GLO1 reduces dicarbonyl stress and attenuates diabetes-induced endothelial dysfunction, impaired neovascularization, and nephropathy (16–19). Similarly, knockdown of GLO1 in rodents is associated with increased MG-H1 levels in the kidney and, even in the face of normoglycemia, is associated with mesangial sclerosis and proteinuria, features typical of diabetic nephropathy (19). These studies suggest that dicarbonyl stress triggers renal pathology directly and independent of glycemia. Whether dicarbonyl stress similarly modulates atherosclerosis is unknown. In this issue of Diabetes, Tikellis et al. (20) examined the atherogenic effects of dicarbonyl and the potential role of RAGE in that process. To that end, they demonstrate that dicarbonyl stress due