title: 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.affiliation: Division of Cardiology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 120-752, Republic of Korea.
authors.forename: Hyelim
authors.initials: H
authors.lastname: Park
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, Republic of Korea.
authors.forename: Sook Hee
authors.initials: SH
authors.lastname: Ku
authors.affiliation: Division of Cardiology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Hyewon
authors.initials: H
authors.lastname: Park
authors.affiliation: Korea Testing & Research Institute, Seoul 150-038, Republic of Korea.
authors.forename: Jueun
authors.initials: J
authors.lastname: Hong
authors.affiliation: Division of Cardiology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea; Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, Republic of Korea.
authors.forename: Dongkyu
authors.initials: D
authors.lastname: Kim
authors.affiliation: Cardiovascular Research Center, Rhode Island Hospital and Brown Medical School, Providence, RI, USA.
authors.forename: Bum-Rak
authors.initials: BR
authors.lastname: Choi
authors.affiliation: Division of Cardiology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Hui-Nam
authors.initials: HN
authors.lastname: Pak
authors.affiliation: Division of Cardiology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Moon-Hyoung
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Department of Bioscience and Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Hyejung
authors.initials: H
authors.lastname: Mok
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Division of Cardiology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Donghoon
authors.initials: D
authors.lastname: Choi
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, Republic of Korea. Electronic address: sunkim@kist.re.kr.
authors.forename: Sun Hwa
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Division of Cardiology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 120-752, Republic of Korea. Electronic address: cby6908@yuhs.ac.
authors.forename: Boyoung
authors.initials: B
authors.lastname: Joung
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000378:metabolism / Q000628:therapy*; D002460:Cell Line; D018031:Connexin 43 / Q000378:metabolism; D018014:Gene Transfer Techniques; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000378:metabolism / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics*; D060449:Wnt Signaling Pathway
chemical_list: D018031:Connexin 43; C580592:Gja1 protein, rat; D034741:RNA, Small Interfering; D000067759:Receptor for Advanced Glycation End Products
keywords: Arrhythmia; Connexin43; Ischemia/reperfusion injury; Receptor for advanced glycation end-products; Wnt1; siRNA