VEGF-B electrotransfer mediated gene therapy induces cardiomyogenesis in a rat model of cardiac ischemia

• Published in: Bioelectrochemistry (Amsterdam, Netherlands) Vol. 124; pp. 105 - 111
• Main Authors: Bulysheva, Anna A., Burcus, Nina, Lundberg, Cathryn G., Francis, Michael P., Heller, Richard
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2018; Elsevier BV
• Subjects: Adults; Arteriosclerosis; Atherosclerosis; Calcium-binding protein; Cardiac muscle; Cardiomyocytes; Cardiomyogenesis; Deoxyribonucleic acid; DNA; Fetuses; Gene electrotransfer; Gene therapy; Gene transfer; Heart; Heart attacks; Immunoreactivity; In vivo methods and tests; Ischemia; Localization; Muscles; Myocardial infarct; Myocardial infarction; Myogenesis; Public health; Regeneration; Rodents; Troponin; Vascular endothelial growth factor; Vascular endothelial growth factor B; Cardiomyogenesis; Myocardial infarct; Gene therapy; Gene electrotransfer; Vascular endothelial growth factor B
• ISSN: 1567-5394; 1878-562X
• DOI: 10.1016/j.bioelechem.2018.07.007

Atherosclerosis induced myocardial infarction (MI) continues to be a major public health concern. Regenerative therapies that restore cardiac muscle cells are largely absent. The rate of cardiomyogenesis in adults is insufficient to compensate for MI damage. In this study, we explored the capacity of a gene therapy approach to promote cardiomyogenesis. We hypothesized that VEGF-B, critical during fetal heart development, could promote cardiomyogenesis in adult ischemic hearts. Gene electrotransfer (GET), a physical method of in vivo gene delivery, was adapted to the rat model of MI. Favorable pulsing parameters were then used for delivery of pVEGF-B and compared to a sham control in terms of infarct size, cardiomyocyte proliferation and presence of new cardiomyocytes. Ki67 immunoreactivity was used for proliferation analysis. Newly synthetized DNA was labeled with BrdU to identify new cells post-infarction. Cardiac troponin co-localization indicated proliferating and new cardiomyocytes histologically. Eight weeks post-treatment, GET pVEGF-B treated hearts had significantly smaller infarcts than the sham control group (p < 0.04). Proliferating and new cardiomyocytes were only present in the GET of pVEGF-B group, and absent in the controls. In summary, GET pVEGF-B promoted cardiomyogenesis post-MI, demonstrating for the first time direct evidence of myocardial regeneration post-infarction. •pVEGF-B gene delivery to left ventricular myocardium was significantly enhanced with gene electrotransfer•pVEGF-B gene expression reduced myocardial infarction size•pVEGF-B gene expression induced cardiac myocyte renewal post myocardial infarction•this is the first report of reversal of damage to the myocardium