Insulinlike growth factor-I induces hypertrophy with enhanced expression of muscle specific genes in cultured rat cardiomyocytes

Abstract

Background. Cardiac hypertrophy is commonly observed in acromegalic patients, in whom serum insulinlike growth factor-I (IGF-I) levels are elevated. In the present study, we examined whether IGF-I induces hypertrophy in cultured neonatal rat cardiomyocytes through its specific receptor and whether IGF binding protein-3 (IGFBP-3), which is a major circulating carrier protein for IGF-I, inhibits IGF-I-induced cardiac hypertrophy in vitro. Methods and Results. Because the response of cardiac hypertrophy is characterized by the induction of expression for muscle-specific genes, the effect of IGF-I on steady-state levels of mRNA for myosin light chain-2 (MLC-2) and troponin I and for skeletal and cardiac α-actin isoforms was evaluated by Northern blot analysis. IGF-I (10-7 M) increased mRNA levels for MLC-2 and troponin I as early as 60 minutes with maximum levels by 6 hours, which were maintained for as long as 24 hours. IGF-I (10-7 M) also increased transcripts for skeletal α-actin but not for cardiac α-actin. The cell size as evaluated morphometrically was almost doubled after 48-hour treatment with IGF-I. IGF-I induction of protein synthesis was dose dependent (10-10 to 10-7 M) with a maximal 2.2-fold increase seen at 10-8 M. In contrast to the hypertrophic effect of IGF-I, growth hormone affected neither protein synthesis nor expression for muscle-specific genes. Binding study using 125I-IGF-I revealed the presence of specific binding sites for IGF-I in rat cardiomyocytes. IGFBP-3 induced a dose-dependent inhibition of protein synthesis stimulated by IGF-I; IGFBP-3 (10-7 M) completely inhibited the [3H]leucine uptake stimulated by IGF-I (10-8 M). IGFBP-3 similarly inhibited the IGF-I-stimulated gene expressions for MLC-2 and troponin I. Conclusions. These results suggest that IGF-I directly causes cardiac hypertrophy and that its effect can be blocked by IGFBP-3.