Cellular mechanisms and consequences of glycation in atherosclerosis and obesity

Abstract

Post-translational modification of proteins imparts diversity to protein functions. The process of glycation represents a complex set of pathways that mediates advanced glycation endproduct (AGE) formation, detoxification, intracellular disposition, extracellular release, and induction of signal transduction. These processes modulate the response to hyperglycemia, obesity, aging, inflammation, and renal failure, in which AGE formation and accumulation is facilitated. It has been shown that endogenous anti-AGE protective mechanisms are thwarted in chronic disease, thereby amplifying accumulation and detrimental cellular actions of these species. Atop these considerations, receptor for advanced glycation endproducts (RAGE)-mediated pathways downregulate expression and activity of the key anti-AGE detoxification enzyme, glyoxalase-1 (GLO1), thereby setting in motion an interminable feed-forward loop in which AGE-mediated cellular perturbation is not readily extinguished. In this review, we consider recent work in the field highlighting roles for glycation in obesity and atherosclerosis and discuss emerging strategies to block the adverse consequences of AGEs. This article is part of a Special Issue entitled: The role of post-translational protein modifications on heart and vascular metabolism edited by Jason R.B. Dyck & Jan F.C. Glatz.

Keywords: Atherosclerosis; Diabetes; Glycation; Obesity; Receptor for advanced glycation end products; Theraepeutics.

Figure 1

The mechanisms of RAGE ligands formation, accumulation and signal transduction. The observation that AGE-RAGE suppresses expression of GLO1 (Glyoxalase 1) suggests that RAGE is both a mechanism for triggering RAGE ligand AGE signal transduction (and cellular consequences) and serves as a feed forward loop to increase AGE production and accumulation.

Figure 2

The mechanisms of soluble RAGE production by cell surface cleavage (by MMPs and ADAM10) and by alternative splicing (formation of esRAGE).