The role of enhanced cardiac fibroblast glycosylation products on collagen synthesis

Abstract

A prominent effect of diabetes on the heart is the development of cardiac fibrosis. High blood glucose levels are known to alter the enzymatic glycosylation of molecules. Enhanced protein (i.e. amino acid) glycosylation levels are known to alter the function of proteins such as transcription factors by interfering in many cases with their regulatory control sites (e.g. enhanced glycosylation at phosphorylation residues). This study was pursued to examine the role that enhanced glycosylation levels has on cardiac fibroblast (CF) collagen production. For this purpose, rat CF were cultured in low and high glucose (HG) conditions. The exposure of CF to HG led to significant increases in collagen production that were associated with alterations in key regulators of extracellular matrix production including TGF‐beta, SMADs and ERK. Exposure to HG also led to increases in total levels of protein glycosylation. The glycosylation levels of the transcription factor SP1 (that importantly regulates collagen promoters) were also enhanced by HG. An adenovirus coding for glycnacase was used to examine the effects of diminished protein glycosylation on CF collagen production and signaling pathways. Results indicate that the reversal of excess glycosylation levels can restore CF collagen production to levels similar to controls. Studies are currently being pursued to identify which alterations of key signaling pathways underlie these beneficial effects.