OVEREXPRESSION OF INSULIN-LIKE GROWTH-FACTOR-I IN THE HEART IS COUPLED WITH MYOCYTE PROLIFERATION IN TRANSGENIC MICE

Transgenic mice were generated in which the cDNA for the human insulin -like growth factor 1B (IGF-1B) was placed under the control of a rat alpha-myosin heavy chain promoter. In mice heterozygous for the transg ene, IGF-1B mRNA was not detectable in the fetal heart at the end of g estation, was present in modest levels at 1 day after birth, and incre ased progressively with postnatal maturation, reaching a peak at 75 da ys. Myocytes isolated from trans,oenic mice secreted 1.15 +/- 0.25 ng of IGF-1 per 10(6) cells per 24 hr versus 0.27 +/- 0.10 ng in myocytes from homozygous wild-type littermates. The plasma level of IGF-1 incr eased 84% in transgenic mice. Heart weight mas comparable in wild-type littermates and transgenic mice up to 45 days of age, but a 42%, 45%, 62%, and 51% increase was found at 75, 135, 210, anal 380 days, respe ctively, after birth, At 45, 75, and 210 days, the number of myocytes in the heart was 21%, 31%, and 55% higher, respectively, in transgenic animals. In contrast, myocyte cell volume was comparable in transgeni c and central mice at all ages. In conclusion, overexpression of IGF-1 in myocytes leads to cardiomegaly mediated by an increased number of cells in the heart.