Epigenetic upregulation of endogenous VEGF-A reduces myocardial infarct size in mice.

6533b7d2fe1ef96bd125ecec

RESEARCH PRODUCT

Epigenetic upregulation of endogenous VEGF-A reduces myocardial infarct size in mice.

Anne Paakinaho Seppo Ylä-herttuala Nihay Laham-karam Erhe Gao Svetlana Laidinen Haja Musthafa Johanna P. Laakkonen Maija Vihinen-ranta Sanna Honkanen Mikko P. Turunen Galina Dragneva Tiia Husso Timo Liimatainen

subject

Male Vascular Endothelial Growth Factor A Small interfering RNA Anatomy and Physiology Transcription Genetic Myocardial Infarction Endogeny Cardiovascular Cardiovascular System Epigenesis Genetic Small hairpin RNA Mice Molecular cell biology Nucleic Acids Gene expression Protein Isoforms RNA Small Interfering Cyclic AMP Response Element-Binding Protein Promoter Regions Genetic Regulation of gene expression Multidisciplinary Chromosome Biology Q R Genomics Gene Therapy Chromatin Interventional Cardiology Cell biology Up-Regulation Vascular endothelial growth factor A Medicine Epigenetics DNA modification Histone modification Research Article Transcriptional Activation Drugs and Devices Science DNA transcription Biology Downregulation and upregulation Genomic Medicine Genetics Gene silencing Animals Gene Silencing Biology Base Sequence Inverted Repeat Sequences ta1182 Membrane Proteins DNA Methylation Phosphoproteins Molecular biology Mice Inbred C57BL RNA Gene expression

description

“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.

year	journal	country	edition	language
2014-01-01	PloS one

10.1371/journal.pone.0089979 https://pubmed.ncbi.nlm.nih.gov/24587164