Inhibition of Cardiac Myocyte Division in c-mycTransgenic Mice

Overexpression of the c-mycprotooncogene in the heart of transgenic mice has been demonstrated to result in cardiac enlargement due to increased myocyte hyperplasia during the fetal period. To determine the age of completion of the proliferative phase of myocyte growth in neonatal mice with c-mycoverexpression, we used a transgenic (TG) mouse model in which c-mycoverexpression is limited to the heart. Bromodeoxyuridine (BrdU) was given to TG and wild type (WT) mice (n=3/group) at 1, 2, 3, 5, 7, 10, 14, 16, 18 and 20 days of age to identify cells in S-phase of the cell cycle. Increased cardiac mass was present in TG compared to WT mice at all time periods (P<0.05). Using computer assisted image analysis, myocardial total nuclear density (NT) in TG mice was 7–31% greater in both the left ventricle (LV) and the interventricular septum (IVS) than in WT at all ages (P<0.05), indicative of a smaller myocyte size. In WT mice, the labeling index (LI) remained almost constant at ≈11–12% until 7 days of age, and then rapidly dropped to ≈2% by 14 days and to less than 1% by 20 days. In contrast, LI in TG dropped continuously from birth to ≈4% at 7 days and ≈2% at 10 days of age (P<0.001). Thus, overexpression of the c-mycprotooncogene is associated with enhanced hyperplastic growth of the heart during fetal development, and accelerated neonatal conversion to hypertrophic myocyte growth.