INSULIN-LIKE-GROWTH-FACTOR-II INDUCES DNA-SYNTHESIS IN FETAL VENTRICULAR MYOCYTES IN-VITRO

Insulin-like growth factor II (IGF2) belongs to a family of growth fac tors that includes insulin and insulin-like growth factor I (IGF1), Al though the accumulating evidence indicates that IGF1 is involved in re gulating proliferation of ventricular myocytes, the role of IGF2 is le ss clear. To gain more insight into the functions of IGF2, rat ventric ular expression of IGF2 mRNA at four developmental stages was examined by Northern analysis. An abundant IGF2 mRNA of approximate to 3.8 kb was detected in fetal ventricles. It was dramatically decreased in neo natal ventricles and became undetectable in juvenile and adult ventric les. Similar expression patterns of the mRNA encoding IGF1 receptor an ti IGF2. receptor were observed. Since the results of Northern analysi s strongly suggest the importance of IGF2 in regulating proliferation of fetal rat ventricular myocytes, the effects of an exogenous IGF2 on DNA synthesis in cultured rat ventricular myocytes were determined. D NA synthesis, which was monitored by measuring 5-bromo-2'-deoxyuridine (BrdU) and [H-3]thymidine incorporation, was increased by twofold to threefold in IGF2-stimulated fetal Ventricular myocytes, whereas no ch ange in BrdU or [H-3]thymidine incorporation was observed in neonatal ventricular myocytes. Instead, IGF2 seemed to induce hypertrophy in ne onatal ventricular myocytes. An antisense oligonucleotide against rat IGF2 mRNA was able to significantly reduce BrdU incorporation, and thi s effect was quantitatively reversed by the addition of exogenous IGF2 . Reversion by exogenous IGF2 was abolished by a monoclonal antibody a gainst IGF1 receptor. In conclusion, our results suggest that IGF2 dir ectly regulates proliferation of fetal rat ventricular myocytes in a p aracrine/autocrine fashion.