title: 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.
abstract: 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.
authors.affiliation: Severance Integrative Research Institute for Cerebral & Cardiovascular Disease, Yonsei University Health System, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, South Korea.
authors.forename: Dongkyu
authors.initials: D
authors.lastname: Kim
authors.forename: Jueun
authors.initials: J
authors.lastname: Hong
authors.forename: Hyung-Ho
authors.initials: HH
authors.lastname: Moon
authors.forename: Hye Yeong
authors.initials: HY
authors.lastname: Nam
authors.forename: Hyejung
authors.initials: H
authors.lastname: Mok
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jeong
authors.forename: Sung Wan
authors.initials: SW
authors.lastname: Kim
authors.forename: Donghoon
authors.initials: D
authors.lastname: Choi
authors.forename: Sun Hwa
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000737:chemistry; D020868:Gene Silencing; D015316:Genetic Therapy; D008297:Male; D009203:Myocardial Infarction / Q000235:genetics / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000378:metabolism; D011094:Polyethyleneimine / Q000008:administration & dosage / Q000737:chemistry; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics*; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000235:genetics / Q000628:therapy*
chemical_list: D034741:RNA, Small Interfering; D003840:Deoxycholic Acid; D011094:Polyethyleneimine; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509250:Ptpn6 protein, rat