Terminally differentiated neonatal rat myocardial cells proliferate and maintain specific differentiated functions following expression of SV40 large T antigen

Early in neonatal development, differentiated myocardial cells lose their ability to proliferate, and further enlargement of the heart occurs through hypertrophy of existing cardiac muscle cells. To study the process of myocardial growth and hypertrophy we have recently utilized a neonatal rat myocardial cell model (Lee, H.R., Henderson, S.A., Reynolds, R., Dunnmon, P., Yuan, D., and Chien, K.R. (1988) J. Biol. Chem. 263, 7352-7538). The present study was designed to determine if the expression of SV40 large T antigen would be capable of restoring the proliferative capacity of terminally differentiated neonatal rat myocardial cells. Utilizing a replication-defective recombinant human adenovirus which contains an SV40 early T antigen insert, maximal expression of T antigen was achieved at 24-48 h postinfection, with over 85-90% of the cells displaying positive T antigen staining. Furthermore, the expression of the T antigen-induced proliferation of the myocardial cells without the loss of expression of certain differentiated properties, including myosin light chain expression and assembly into organized myofibrils, spontaneous contractile activity, and a chronotropic response to adrenergic agonists. These results demonstrate the utility of recombinant human adenoviruses to achieve high efficiency transient expression of foreign genes in differentiated myocardial cells and suggest that the expression of T antigen may provide a suitable model to study the biochemical events which are required to maintain the proliferative capacity of myocardial cells.