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

 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 OF CONTROLLED RELEASE, Vol.217 : 315-326, 2015 
Journal Title
Issue Date
Animals ; Arrhythmias, Cardiac/etiology ; Arrhythmias, Cardiac/metabolism ; Arrhythmias, Cardiac/therapy* ; Cell Line ; Connexin 43/metabolism ; Gene Transfer Techniques ; Male ; Myocardial Reperfusion Injury/complications ; Myocardial Reperfusion Injury/metabolism ; Myocardial Reperfusion Injury/therapy* ; Myocardium/metabolism ; RNA, Small Interfering/administration & dosage* ; Rats, Sprague-Dawley ; Receptor for Advanced Glycation End Products/genetics* ; Wnt Signaling Pathway
Arrhythmia ; Connexin43 ; Ischemia/reperfusion injury ; Receptor for advanced glycation end-products ; Wnt1 ; siRNA
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.
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1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Dong Kyu(김동규)
Park, Hye Lim(박혜림)
Park, Hye Won(박혜원)
Pak, Hui Nam(박희남) ORCID logo https://orcid.org/0000-0002-3256-3620
Lee, Moon Hyoung(이문형) ORCID logo https://orcid.org/0000-0002-7268-0741
Joung, Bo Young(정보영) ORCID logo https://orcid.org/0000-0001-9036-7225
Choi, Dong Hoon(최동훈) ORCID logo https://orcid.org/0000-0002-2009-9760
Hong, Ju Eun(홍주은)
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