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Anti-apoptotic cardioprotective effects of SHP-1 gene silencing against ischemia–reperfusion injury: Use of deoxycholic acid-modified low molecular weight polyethyleneimine as a cardiac siRNA-carrier

 Dongkyu Kim  ;  Jueun Hong  ;  Hyung-Ho Moon  ;  Hye Yeong Nam  ;  Hyejung Mok  ;  Ji Hoon Jeong  ;  Sung Wan Kim  ;  Donghoon Choi  ;  Sun Hwa Kim 
 JOURNAL OF CONTROLLED RELEASE, Vol.168(2) : 125-134, 2013 
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SHP-1 siRNA ; Myocardial apoptosis ; Deoxycholic acid ; Low molecular weight PEI ; Myocardial ischemia–reperfusion injury
The cardiomyocyte apoptosis plays a critical role in the development of myocardial injury after ischemia and reperfusion. Thus, alteration of the major apoptosis-regulatory factors during myocardial ischemia-reperfusion is expected to have favorable cardioprotective effects. Herein, we report ischemic-reperfused myocardial infarction (MI) repair with siRNA against Src homology region 2 domain-containing tyrosine phosphatase-1 (SHP-1), which is known as a key factor involved in regulating the progress of apoptosis in many cell types. A low molecular weight polyethyleneimine modified with deoxycholic acid (PEI1.8-DA)-based delivery strategy was suggested for the cardiac application of SHP-1 siRNA to overcome the poor gene delivery efficiency to myocardium due to the highly charged structures of the compact cardiac muscles. The PEI1.8-DA conjugates formed stable nanocomplexes with SHP-1 siRNA via electrostatic and hydrophobic interactions. The PEI1.8-DA/SHP-1 siRNA polyplexes effectively silenced SHP-1 gene expression in cardiomyocytes, leading to a significant inhibition of cardiomyocyte apoptosis under hypoxia. In comparison to conventional gene carriers, relatively large amounts of siRNA molecules remained after treatment with the PEI1.8-DA/SHP-1 siRNA polyplexes. Cardiac administration of the PEI1.8-DA/SHP-1 siRNA polyplexes resulted in substantial improvement in SHP-1 gene silencing, which can be explained by the enhancement of cardiac delivery efficiency of the PEI1.8-DA conjugates. In addition, in vivo treatment with the PEI1.8-DA/SHP-1 siRNA polyplexes induced a highly significant reduction in myocardial apoptosis and infarct size in rat MI models. These results demonstrate that the PEI1.8-DA/SHP-1 siRNA polyplex formulation is a useful system for efficient gene delivery into the compact myocardium that provides a fundamental advantage in treating ischemic-reperfused MI.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kim, Dong Kyu(김동규)
Moon, Hyung Ho(문형호)
Choi, Dong Hoon(최동훈) ORCID logo https://orcid.org/0000-0002-2009-9760
Hong, Ju Eun(홍주은)
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