Insulin-like 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 insulin-like 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 alpha-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 alpha-actin but not for cardiac alpha-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.

E2F-1 Regulates the Expression of a Subset of Target Genes during Skeletal Myoblast Hypertrophy

“…The hypertrophic response is initiated by a range of stimuli such as growth factors, hormones, cytokines, vasoactive peptides, and catecholamines (53)(54)(55)(56)(57)(58), and while the intracellular pathways that are activated may distinguish pathologic from physiologic cell growth (59,60) it is likely that these pathways converge on common events affecting cell growth, architecture, and metabolic requirements. We previously demonstrated that several hypertrophic stimuli, including AngII, isoproterenol, prostaglandin F 2␣ , insulin-like growth factor-1, and 1,25-dihydroxyvitamin D 3 , are capable of inducing cell growth without division in C2C12 myoblasts and that all of these result in Rb phosphorylation specifically at serine 780 (10).…”

Electrical stimulation of neonatal cardiomyocytes results in the sequential activation of nuclear genes governing mitochondrial proliferation and differentiation

“…Contractile stimulation of cardiac myocytes in serum-free culture results in cardiac growth and increased myofibrillar organization in vitro, suggesting that the alterations in myofibrillar content may occur by an autocrine pathway (29,30). The mechanism by which increases in the contraction rate-e.g., by long-term electrical stimulationinfluences the process of cardiac growth and differentiation is an intense area of investigation.…”

“…Other investigators have demonstrated that mechanical stretch activates phosphorylation cascades, including protein kinase C, mitogen-activated protein kinases and p90rsk (27). Cardiac myocyte hypertrophy can also be evoked by exogenous factors including angiotensin II (31), ␣-agonists, and insulin-like growth factors (29,30).…”

Cardiac Effects of Growth Hormone in Physiology and in Heart Failure

“…In cultured cardiomyocytes, IGF-I stimulates protein synthesis and cardiac cell size [4]; in contrast, if the expression of IGF-I is blocked, protein synthesis and DNA replication are blocked. There is extensive animal data supporting a role of the growth hormone/IGF-I axis in the control of cardiac cell growth.…”