Receptor for Advanced Glycation End Products Suppressed Arrhythmia by Reducing Infarct Size and Fibrosis in Ischemia Reperfusion Rat Model

Abstract

Background and Objectives: The role of the receptor for advanced glycation end products (RAGE) blockers in the arrhythmogenic effect after myocardial infarction remains unclear. In this study, we evaluated the anti-arrhythmogenic effects of RAGE in an ischemia reperfusion (IR) model. Subject and Methods: IR was performed by ligation of the left anterior descending artery for 1 h in 8-week-old male Sprague-Dawley rats. A RAGE-siRNA polyplex combined with a polyethyleneiminemodified with deoxycholic acid (PEI-DA) was delivered to the heart. Rats were randomly divided into the following four groups: 1) control (sham operation, n=10), 2) IR (IR only, n=11), 3) IR+siRAGE (IR and RAGE-siRNA injection, n=10), and 4) IR+scRNA (IR and scrambled siRNA injection, n=9). Results: In the IR group, 6 (55%) of 11 rats died suddenly at 46 ± 14 min after acute myocardial infarction. However, no rats died in the control or IR+siRAGE groups. The IR+siRAGE group showed a better survival rate than the IR group (p=0.03). IR+siRAGE prevented arrhythmia (10% vs. 50%, p=0.02) compared with IR only. In Langendorff-perfused rat hearts, the IR+siRAGE group showed decreased action potential duration (121 ± 10, vs. 162 ± 60 ms, p=0.001), maximum slope of the action potential duration restitution curve (0.34 ± 0.09 vs. 1.14 ± 0.26, p<0.001), and inducible ventricular tachycardia (0% vs. 71%, p=0.01) compared to the IR group. However, these protective effects were not observed in the IR+scRNA group. The IR+siRAGE group showed significantly reduced infarct size and fibrosis compared to the IR group. Conclusion: RAGE-siRNA polyplexes combined with polyethyleneimine-modified with deoxycholic acid suppressed arrhythmia by reducing infarct size and fibrosis in a rat IR model.