Molecular mechanisms of AGE/RAGE-mediated fibrosis in the diabetic heart

Abstract

Chronic hyperglycemia is one of the main characteristics of diabetes. Persistent exposure to elevated glucose levels has been recognized as one of the major causal factors of diabetic complications. In pathologies, like type 2 diabetes mellitus (T2DM), mechanical and biochemical stimuli activate profibrotic signaling cascades resulting in myocardial fibrosis and subsequent impaired cardiac performance due to ventricular stiffness. High levels of glucose nonenzymatically react with long-lived proteins, such as collagen, to form advanced glycation end products (AGEs). AGE-modified collagen increase matrix stiffness making it resistant to hydrolytic turnover, resulting in an accumulation of extracellular matrix (ECM) proteins. AGEs account for many of the diabetic cardiovascular complications through their engagement of the receptor for AGE (RAGE). AGE/RAGE activation stimulates the secretion of numerous profibrotic growth factors, promotes increased collagen deposition leading to tissue fibrosis, as well as increased RAGE expression. To date, the AGE/RAGE cascade is not fully understood. In this review, we will discuss one of the major fibrotic signaling pathways, the AGE/RAGE signaling cascade, as well as propose an alternate pathway via Rap1a that may offer insight into cardiovascular ECM remodeling in T2DM. In a series of studies, we demonstrate a role for Rap1a in the regulation of fibrosis and myofibroblast differentiation in isolated diabetic and non-diabetic fibroblasts. While these studies are still in a preliminary stage, inhibiting Rap1a protein expression appears to down-regulate the molecular switch used to activate the ζ isotype of protein kinase C thereby promote AGE/RAGE-mediated fibrosis.

Keywords: Type 2 diabetes mellitus, Cardiac fibrosis, Fibroblasts, Advanced glycation end product, Rap1a, Extracellular matrix

Core tip: Chronic hyperglycemia is a characteristic of diabetes and one of the major causal factors of diabetic complications. In type 2 diabetes mellitus, mechanical and biochemical stimuli activated profibrotic signaling cascades resulting in myocardial fibrosis, impaired cardiac performance, and ventricular stiffness. Glucose nonenzymatically reacts with extracellular matrix (ECM) proteins forming advanced glycation end products (AGEs). AGE-modified collagen increases matrix accumulation and stiffness by engaging the receptor for AGE (RAGE), the receptor for AGE. To date, our understanding of the AGE/RAGE cascade remains imprecise. This review discusses the AGE/RAGE signaling cascade and proposes an alternate role for Rap1a in diabetic cardiovascular ECM remodeling.