RAGE siRNA-mediated gene silencing provides cardioprotection against ventricular arrhythmias in acute ischemia and reperfusion.

Abstract

Expression of receptor for advanced glycation end-products (RAGE) is suggested to play a crucial role in mediating cardiac ischemia/reperfusion (IR) injury, and the blockade of RAGE signaling has been considered as a potential therapeutic strategy for the treatment of IR-induced cardiac damage. In this study, we primarily investigated the effects of RAGE suppression particularly on IR-induced ventricular arrhythmia. To inhibit the IR-induced upregulation of RAGE, siRNA targeting RAGE (siRAGE) was delivered to myocardium by using deoxycholic acid-modified polyethylenimine (PEI-DA) as a non-viral gene carrier. The resultant PEI-DA/siRAGE nanocomplexes successfully silenced the expression of RAGE and attenuated the inflammation and apoptosis in the ischemic-reperfused myocardium. According to our results, the electrophysiological properties (e.g., action potential propagation, action potential duration, and conduction velocity), disrupted by IR injury, were restored to normal level and the induction of ventricular tachycardia was abolished by RAGE silencing. We further found that RAGE suppression led to the activation of Wnt signaling, followed by the expression of gap junction protein, connexin43. Thus it could be concluded that successful siRAGE delivery is protective against IR-induced ventricular arrhythmia.

• Authors: Hyelim Park, Sook Hee Ku, Hyewon Park, Jueun Hong, Dongkyu Kim, Bum-Rak Choi, Hui-Nam Pak, Moon-Hyoung Lee, Hyejung Mok, Ji Hoon Jeong, Donghoon Choi, Sun Hwa Kim, Boyoung Joung
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 217 Pg. 315-26 (Nov 10 2015) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 26381899 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Connexin 43
• Gja1 protein, rat
• RNA, Small Interfering
• Receptor for Advanced Glycation End Products

Topics

• Animals
• Arrhythmias, Cardiac (etiology, metabolism, therapy)
• Cell Line
• Connexin 43 (metabolism)
• Gene Transfer Techniques
• Male
• Myocardial Reperfusion Injury (complications, metabolism, therapy)
• Myocardium (metabolism)
• RNA, Small Interfering (administration & dosage)
• Rats, Sprague-Dawley
• Receptor for Advanced Glycation End Products (genetics)
• Wnt Signaling Pathway