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 ΞΆ isotype of
protein kinase C thereby promote AGE/RAGE-mediated
fibrosis.