title: Simultaneous regulation of apoptotic gene silencing and angiogenic gene expression for myocardial infarction therapy: Single-carrier delivery of SHP-1 siRNA and VEGF-expressing pDNA.
abstract: Gene therapy is aimed at selectively knocking up or knocking down the target genes involved in the development of diseases. In many human diseases, dysregulation of disease-associated genes is occurred concurrently: some genes are abnormally turned up and some are turned down. In the field of non-viral gene therapy, plasmid DNA (pDNA) and small interfering RNA (siRNA) are suggested as representative regulation tools for activating and silencing the expression of genes of interest, representatively. Herein, we simultaneously loaded both siRNA (Src homology region 2 domain-containing tyrosine phosphatase-1 siRNA, siSHP-1) for anti-apoptosis and pDNA (hypoxia-inducible vascular endothelial growth factor expression vector, pHI-VEGF) for angiogenesis in a single polymeric nanocarrier and used to synergistically attenuate ischemia-reperfusion (IR)-induced myocardial infarction, which is mainly caused by dysregulating of cardiac apoptosis and angiogenesis. For dual-modality cardiac gene delivery, siSHP-1 and pHI-VEGF were sequentially incorporated into a stable nanocomplex by using deoxycholic acid-modified polyethylenimine (DA-PEI). The resulting DA-PEI/siSHP-1/pHI-VEGF complexes exhibited the high structural stability against polyanion competition and the improved resistance to digestion by nucleases. The cardiac administration of DA-PEI/siSHP-1/pHI-VEGF reduced cardiomyocyte apoptosis and enhanced cardiac microvessel formation, thereby reducing infarct size in rat ischemia-reperfusion model. The simultaneous anti-apoptotic and angiogenic gene therapies synergized the cardioprotective effects of each strategy; thus our dual-modal single-carrier gene delivery system can be considered as a promising candidate for treating ischemic heart diseases.
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea; Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University Health System, Seoul 120-752, South Korea.
authors.forename: Dongkyu
authors.initials: D
authors.lastname: Kim
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea.
authors.forename: Sook Hee
authors.initials: SH
authors.lastname: Ku
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 136-701, South Korea.
authors.forename: Hyosuk
authors.initials: H
authors.lastname: Kim
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea; School of Pharmacy, Sungkyunkwan University, Suwon 440-746, South Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, Seoul 133-791, South Korea.
authors.forename: Minhyung
authors.initials: M
authors.lastname: Lee
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea; School of Pharmacy, Sungkyunkwan University, Suwon 440-746, South Korea.
authors.forename: Ick Chan
authors.initials: IC
authors.lastname: Kwon
authors.affiliation: Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University Health System, Seoul 120-752, South Korea. Electronic address: cdhlyj@yuhs.ac.
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, South Korea. Electronic address: sunkim@kist.re.kr.
authors.forename: Sun Hwa
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D004247:DNA / Q000008:administration & dosage; D003840:Deoxycholic Acid / Q000737:chemistry; D004195:Disease Models, Animal; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D008297:Male; D009203:Myocardial Infarction / Q000235:genetics / Q000628:therapy*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000628:therapy; D018919:Neovascularization, Physiologic / Q000235:genetics; D010957:Plasmids; D011094:Polyethyleneimine / Q000008:administration & dosage / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D003840:Deoxycholic Acid; D011094:Polyethyleneimine; D004247:DNA
keywords: Deoxycholic acid-modified polyethylenimine; Myocardial ischemia-reperfusion injury; SHP-1 siRNA; VEGF plasmid DNA