Cardiomyocyte hyperplasia after plasmid-mediated vascular endothelial growth factor gene transfer in pigs with chronic myocardial ischemia

• Published in: The journal of gene medicine Vol. 6; no. 2; pp. 222 - 227
• Main Authors: Laguens, Rubén, Cabeza Meckert, Patricia, Vera Janavel, Gustavo, De Lorenzi, Andrea, Lascano, Elena, Negroni, Jorge, del Valle, Héctor, Cuniberti, Luis, Martínez, Verónica, Dulbecco, Eduardo, Melo, Carlos, Fernández, Nahuel, Criscuolo, Marcelo, Crottogini, Alberto
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.02.2004; Wiley Periodicals Inc
• Subjects: Animals; cardiomyocyte hyperplasia; cytokinesis; Gene therapy; Gene Transfer Techniques; myocardial ischemia; Myocardial Ischemia - therapy; myocyte proliferation; Myocytes, Cardiac - metabolism; pigs; Reverse Transcriptase Polymerase Chain Reaction; Swine - metabolism; vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; VEGF
• ISSN: 1099-498X; 1521-2254
• DOI: 10.1002/jgm.478

Background For over 40 years it has been proposed that cardiomyocyte hyperplasia may occur in hypertrophic human hearts. While this implies that heart myocytes can undergo cytokinesis, evidence of conventional cell division has been exceptionally reported. Recently, we found that gene transfer of vascular endothelial growth factor (VEGF) displays a mitogenic effect on adult cardiomyocytes. In the present study we searched for cardiomyocyte hyperplasia as evidence of VEGF‐induced cardiomyocyte cytokinesis. Methods Three weeks after implanting an Ameroid constrictor at the origin of the left circumflex artery, 16 pigs were randomized to receive 10 direct intramyocardial injections of 3.8 mg of plasmid encoding for VEGF (pVEGF) or empty plasmid. Five weeks later, hearts were weighed, myocyte diameter was measured in tissue sections, and myocyte length and nuclei number were studied in isolated myocytes. A resting echocardiogram was performed immediately before reoperation and before sacrifice to evaluate global and regional left ventricular function. Investigators were blinded to the study groups and nature of the injectate until the end of data analysis. Results No heart weight differences existed between groups. However, in the ischemic myocardium, pVEGF‐treated hearts had 22% more cardiomyocytes per unit volume and exhibited significantly more oligonucleated (1 or 2 nuclei) cardiomyocytes than hearts receiving empty plasmid. Conclusions In pigs with chronic myocardial ischemia, VEGF gene transfer induced cardiomyocyte cytokinesis, as revealed by cardiomyocyte hyperplasia. Our finding extends the previously reported mitogenic effect of VEGF on adult cardiomyocytes and supports the hypothesis that VEGF may have a therapeutic role in diseases characterized by myocardial cell loss. Copyright © 2004 John Wiley & Sons, Ltd.