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


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.
Ito
H
H
Second Department of Internal Medicine, Tokyo Medical and Dental University, Japan.
Hiroe
M
M
Hirata
Y
Y
Tsujino
M
M
Adachi
S
S
Shichiri
M
M
Koike
A
A
Nogami
A
A
Marumo
F
F
D000199:Actins / Q000235:genetics; D000818:Animals; D001667:Binding, Competitive; D006332:Cardiomegaly / Q000139:chemically induced* / Q000235:genetics*; D002352:Carrier Proteins / Q000494:pharmacology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology*; D007536:Isomerism; D007930:Leucine / Q000493:pharmacokinetics; D009132:Muscles / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009218:Myosins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014336:Troponin / Q000235:genetics; D019210:Troponin I
D000199:Actins; D002352:Carrier Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D012333:RNA, Messenger; D014336:Troponin; D019210:Troponin I; D007334:Insulin-Like Growth Factor I; D009218:Myosins; D007930:Leucine