title: Epigenetic upregulation of endogenous VEGF-A reduces myocardial infarct size in mice.
abstract: "Epigenetherapy" alters epigenetic status of the targeted chromatin and modifies expression of the endogenous therapeutic gene. In this study we used lentiviral in vivo delivery of small hairpin RNA (shRNA) into hearts in a murine infarction model. shRNA complementary to the promoter of vascular endothelial growth factor (VEGF-A) was able to upregulate endogenous VEGF-A expression. Histological and multiphoton microscope analysis confirmed the therapeutic effect in the transduced hearts. Magnetic resonance imaging (MRI) showed in vivo that the infarct size was significantly reduced in the treatment group 14 days after the epigenetherapy. Importantly, we show that promoter-targeted shRNA upregulates all isoforms of endogenous VEGF-A and that an intact hairpin structure is required for the shRNA activity. In conclusion, regulation of gene expression at the promoter level is a promising new treatment strategy for myocardial infarction and also potentially useful for the upregulation of other endogenous genes.
authors.affiliation: Department of Biotechnology and Molecular Medicine, A.I.Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: Mikko P
authors.initials: MP
authors.lastname: Turunen
authors.affiliation: Department of Biotechnology and Molecular Medicine, A.I.Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: Tiia
authors.initials: T
authors.lastname: Husso
authors.affiliation: Department of Biotechnology and Molecular Medicine, A.I.Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: Haja
authors.initials: H
authors.lastname: Musthafa
authors.affiliation: Department of Biotechnology and Molecular Medicine, A.I.Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Laidinen
authors.affiliation: Department of Biotechnology and Molecular Medicine, A.I.Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: Galina
authors.initials: G
authors.lastname: Dragneva
authors.affiliation: Department of Biotechnology and Molecular Medicine, A.I.Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: Nihay
authors.initials: N
authors.lastname: Laham-Karam
authors.affiliation: Department of Biotechnology and Molecular Medicine, A.I.Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Honkanen
authors.affiliation: Department of Biotechnology and Molecular Medicine, A.I.Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Paakinaho
authors.affiliation: Department of Biotechnology and Molecular Medicine, A.I.Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: Johanna P
authors.initials: JP
authors.lastname: Laakkonen
authors.affiliation: The Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, Finland.
authors.forename: Maija
authors.initials: M
authors.lastname: Vihinen-Ranta
authors.affiliation: Department of Biotechnology and Molecular Medicine, A.I.Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Liimatainen
authors.affiliation: Department of Biotechnology and Molecular Medicine, A.I.Virtanen Institute, University of Eastern Finland, Kuopio, Finland ; Research Unit and Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
mesh_terms: D000818:Animals; D001483:Base Sequence; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D055029:Inverted Repeat Sequences / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010750:Phosphoproteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation; D015854:Up-Regulation / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D008565:Membrane Proteins; C498709:Pag1 protein, mouse; D010750:Phosphoproteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A