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

Dongkyu Kim, Sook Hee Ku, Hyosuk Kim, Ji Hoon Jeong, Minhyung Lee, Ick Chan Kwon, Donghoon Choi, Sun Hwa Kim

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)182-194
Number of pages13
JournalJournal of Controlled Release
Volume243
DOIs
Publication statusPublished - 2016 Dec 10

Fingerprint

Gene Silencing
Vascular Endothelial Growth Factor A
Small Interfering RNA
Plasmids
Polyethyleneimine
Myocardial Infarction
Deoxycholic Acid
Gene Expression
Genetic Therapy
DNA
Apoptosis
Genes
Reperfusion
Ischemia
Therapeutics
Gene Transfer Techniques
src Homology Domains
Microvessels
Phosphoric Monoester Hydrolases
Cardiac Myocytes

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Cite this

@article{9b30158ee21840489b6abe49099c5bfe,
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.",
author = "Dongkyu Kim and Ku, {Sook Hee} and Hyosuk Kim and Jeong, {Ji Hoon} and Minhyung Lee and Kwon, {Ick Chan} and Donghoon Choi and Kim, {Sun Hwa}",
year = "2016",
month = "12",
day = "10",
doi = "10.1016/j.jconrel.2016.10.017",
language = "English",
volume = "243",
pages = "182--194",
journal = "Journal of Controlled Release",
issn = "0168-3659",
publisher = "Elsevier",

}

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. / Kim, Dongkyu; Ku, Sook Hee; Kim, Hyosuk; Jeong, Ji Hoon; Lee, Minhyung; Kwon, Ick Chan; Choi, Donghoon; Kim, Sun Hwa.

In: Journal of Controlled Release, Vol. 243, 10.12.2016, p. 182-194.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Simultaneous regulation of apoptotic gene silencing and angiogenic gene expression for myocardial infarction therapy

T2 - Single-carrier delivery of SHP-1 siRNA and VEGF-expressing pDNA

AU - Kim, Dongkyu

AU - Ku, Sook Hee

AU - Kim, Hyosuk

AU - Jeong, Ji Hoon

AU - Lee, Minhyung

AU - Kwon, Ick Chan

AU - Choi, Donghoon

AU - Kim, Sun Hwa

PY - 2016/12/10

Y1 - 2016/12/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84993982634&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84993982634&partnerID=8YFLogxK

U2 - 10.1016/j.jconrel.2016.10.017

DO - 10.1016/j.jconrel.2016.10.017

M3 - Article

C2 - 27765623

AN - SCOPUS:84993982634

VL - 243

SP - 182

EP - 194

JO - Journal of Controlled Release

JF - Journal of Controlled Release

SN - 0168-3659

ER -