Abstract 11872: Receptor for Advanced Glycation End Products Silencing Suppress Arrhythmia and Improve Electrical Conduction by Increasing Connexin43 via Wnt1 Activation in Rat Model for Ischemia Reperfusion Injury
Introduction: Expression of receptor for advanced glycation end products (RAGE) plays a crucial role in mediating cardiac ischemia/reperfusion (I/R) injury. Although the detailed mechanisms are unknown, RAGE silencing has been suggested as a cardioprotective therapy. I/R injury is related to increased GSK 3β, and Wnt family of genes is one of the regulators of gap junction expression and function.
Hypothesis: This study evaluated the effect of RAGE silencing on electrical conduction, arrhythmia, connexin43 (Cx43) and Wnt activation in rat I/R injury model.
Methods: Sprague-Dawley rats underwent 1 hour of ligation of the left anterior descending artery, followed by reperfusion for 2 hours (I/R, n=11). RAGE-siRNA/PEI-DA nanocarriers were treated after I/R injury for RAGE silencing (I/R+RAGE, n=10), and scrambled RNA for the discrimination of RNA effect (I/R+scRNA, n=9). Hearts were perfused, optically mapped to analyze action potential durations (APD), intracellular Ca2+ transients, and restitution kinetics (RK), and tested for VF vulnerability.
Results: Compared with control (n=10), I/R rats had shorter APD, slower conduction velocity (CV; p<0.01) and steeper CV-RK, higher level of proteins for tumor necrosis factor-α and interleukin 6, and RAGE. RAGE-siRNA/PEI-DA nanocarrier treatment has reversed the translations for inflammation and the level of RAGE, increased CV (p<0.01), flattened CV-RK, and increased APD at 90% recovery to baseline. Programed stimulation triggered VT/VF in I/R (71%), but not in control (0%) and I/R+RAGE (0%, p<0.001 versus I/R). I/R injury increased the expression of GSK 3β, and reduced Wnt1, β-catenin and Cx43. However, RAGE silencing decreased the expression of GSK 3β, and enhanced Wnt1, β-catenin and Cx43 (p<0.05).
Conclusions: RAGE silencing therapy suppressed VT/VF in I/R hearts by increasing CV from a combination of the inhibition of GSK 3β and enhancing Wnt1, β-catenin and Cx43 in rat model for I/R injury.
Author Disclosures: H. Park: None. H. Park: None. J. Lim: None. H. Pak: None. M. Lee: None. D. Choi: None. S. Kim: None. B. Joung: None.
- © 2014 by American Heart Association, Inc.