title: 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.
authors.affiliation: Jia Zhao, Rushil Randive, James A Stewart, Department of Biological Sciences, Mississippi State University, Mississippi State, MS 39762, United States.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Jia Zhao, Rushil Randive, James A Stewart, Department of Biological Sciences, Mississippi State University, Mississippi State, MS 39762, United States.
authors.forename: Rushil
authors.initials: R
authors.lastname: Randive
authors.affiliation: Jia Zhao, Rushil Randive, James A Stewart, Department of Biological Sciences, Mississippi State University, Mississippi State, MS 39762, United States.
authors.forename: James A
authors.initials: JA
authors.lastname: Stewart
keywords: Advanced glycation end product; Cardiac fibrosis; Extracellular matrix; Fibroblasts; Rap1a; Type 2 diabetes mellitus