Abstract 176: Intravenous Infusion Of Glycated End Products Induces Cardiac Remodeling And Fibrosis Through RAGE Mediated Oxidative Stress
Advanced glycation end products (AGEs) play a major role in the development of cardiovascular disorders in diabetic patients. Growing evidence has shown that the western diet is a plentiful source of exogenous AGEs. However, the direct impact of these AGEs on cardiac remodeling process is not well understood. Thus, the present study was intended to scrutinize the long term effects of circulating AGEs on cardiac extracellular matrix alterations both in vivo, Wistar rats, and in vitro, H9C2(2-1) cardiac myofibroblast cells. In vivo Rats (n=8/group) were administered with an intravenous infusion of in vitro prepared glycated-RSA (AGEs-RSA) (50 mg/kg /day for 30 days), while control animals received the non-glycated-RSA. In vitro, H9C2 (2-1) cardiac myofibroblast cells were exposed to AGEs (100µg/ml) for 24 hours. Upon AGEs infusion, a significant increase in fibrosis (3-fold, p<0.01) with increased expression of matrix genes MMP-2 and -9 (P<0.01, respectively), CTGF (p<0.01) and TGF-β (P<0.01) was found in the heart tissues compared to non-glycated-RSA infused rats. Furthermore, an increase in mRNA and protein expression of RAGE (receptor for AGE), and NADPH oxidase (NOX-p47 phox subunit), iNOS and NF-κB was observed in the heart tissue of AGEs infused rats. Furthermore, induction of lipid peroxides (p<0.001) were also found in the heart tissue of AGEs-RSA infused rats. Similarly, H9C2 (2-1) cells exposed to AGEs-RSA demonstrated a significant increase in ROS release (DCF fluorescence, p<0.001) with augmented expression of RAGE (P<0.01) and NOX-p47 phox (p<0.001) compared to untreated cells. Whereas, cells pre-treated with N-Acetyl cysteine and RAGE neutralizing antibody significantly impeded the NOX expression (p<0.01) and attenuated the up-regulation of RAGE and NF-κB in AGEs-RSA treated H9C2 cells. Thus, the results of the present study demonstrated the deleterious effect of AGEs that directly induces oxidative stress and matrix derangement in heart tissue even when ingested through exogenous sources.
- © 2013 by American Heart Association, Inc.