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Plasmid-mediated VEGF gene transfer induces cardiomyogenesis and reduces myocardial infarct size in sheep

Abstract

We have recently reported that in pigs with chronic myocardial ischemia heart transfection with a plasmid encoding the 165 isoform of human vascular endothelial growth factor (pVEGF165) induces an increase in the mitotic index of adult cardiomyocytes and cardiomyocyte hyperplasia. On these bases we hypothesized that VEGF gene transfer could also modify the evolution of experimental myocardial infarct. In adult sheep pVEGF165 (3.8 mg, n=7) or empty plasmid (n=7) was injected intramyocardially 1 h after coronary artery ligation. After 15 days infarct area was 11.3±1.3% of the left ventricle in the VEGF group and 18.2±2.1% in the empty plasmid group (P<0.02). The mechanisms involved in infarct size reduction (assessed in additional sheep at 7 and 10 days after infarction) included an increase in early angiogenesis and arteriogenesis, a decrease in peri-infarct fibrosis, a decrease in myofibroblast proliferation, enhanced cardiomyoblast proliferation and mitosis of adult cardiomyocytes with occasional cytokinesis. Resting myocardial perfusion (99mTc-sestamibi SPECT) was higher in VEGF-treated group than in empty plasmid group 15 days after myocardial infarction. We conclude that plasmid-mediated VEGF gene transfer reduces myocardial infarct size by a combination of effects including neovascular proliferation, modification of fibrosis and cardiomyocyte regeneration.

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Acknowledgements

This work was supported by grants from The René G Favaloro University Foundation and by grant PID #268 from the Argentine National Agency for Scientific and Technological Promotion (ANPCyT), Secretariat for Technology, Science and Productive Innovation (SeTCIP). Drs Crottogini and Laguens are established Investigators of National Council for Scientific and Technical Investigations (CONICET). We thank technicians Julio Martínez, Fabián Gauna and Marcela Álvarez, veterinarians María Besansón, Pedro Iguain and Marta Tealdo and animal house personnel Juan Ocampo, Osvaldo Sosa and Juan Mansilla.

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Correspondence to R Laguens.

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Vera Janavel, G., Crottogini, A., Cabeza Meckert, P. et al. Plasmid-mediated VEGF gene transfer induces cardiomyogenesis and reduces myocardial infarct size in sheep. Gene Ther 13, 1133–1142 (2006). https://doi.org/10.1038/sj.gt.3302708

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