Do Advanced Glycation End products (AGEs) play a role in heart failure? (R-5960)

Heart failure (HF) results from a series of complex processes that are still incompletely understood. Treatments of HF patients tend to relieve symptomatic disorders, improve outcome but fail to completely reverse the adverse phenotype. Several clinical and experimental studies support the view that Advanced Glycation End products (AGEs) have a significant role in cardiac dysfunction. AGEs are a heterogeneous family of compounds, composed of proteins and lipids that become non-enzymatically glycated and oxidized after persistent contact with aldose sugar and/or a high degree of oxidative stress. Many studies suggest that increased circulating AGEs and tissue accumulation are not only limited to the diabetic setting but are involved in HF progression. The deleterious effect of AGEs on cardiac performance has been mainly attributed to "indirect mechanisms" through worsening vasculature and extracellular matrix properties, rather than a direct effect on cardiomyocytes, despite the presence of their receptors (i.e. RAGE) in myocyte sarcolemma. To date, cellular effects of AGEs in cardiac tissue remain elusive. The objective of this project is to understand how AGEs and AGEs-RAGE interactions lead to cardiac dysfunction. We hypothesize that (1) AGEs-RAGE interaction leads to cardiomyocyte dysfunction directly, that (2) sustained increase in circulating AGEs level leads to global cardiac impairment and (3) propose AGEs to be potent early biomarkers for HF, useful in the clinic.

Keywords:TISSUE CULTURE

Disciplines:Biophysics