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.
Bibliographical noteFunding Information:
This study was supported in part by research grants from the Korean Heart Rhythm Society ( 2011-3 ); the Basic Science Research Program ( NRF-2010-0021993 , NRF-2012R1A2A2A02045367 ) and GiRC program ( 2012K1A1A2A01056095 ; 2012K1A1A2A01056094 ) through the National Research Foundation of Korea ; the Korean Healthcare technology R&D project ( HI12C1552 ) funded by Ministry of Health & Welfare ; and the Intramural Research Program of KIST .
© 2015 Elsevier B.V.
All Science Journal Classification (ASJC) codes
- Pharmaceutical Science