INSULIN-LIKE GROWTH FACTOR-I INDUCES HYPERTROPHY WITH ENHANCED EXPRESSION OF MUSCLE-SPECIFIC GENES IN CULTURED RAT CARDIOMYOCYTES
INSULIN-LIKE GROWTH FACTOR-I INDUCES HYPERTROPHY WITH ENHANCED EXPRESSION OF MUSCLE-SPECIFIC GENES IN CULTURED RAT CARDIOMYOCYTES
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DOI：
10.1161/01.cir.87.5.1715
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发表时间：
1993-05-01
期刊：
影响因子：
37.8
通讯作者：
MARUMO, F
中科院分区：
文献类型：
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作者：
ITO, H;HIROE, M;MARUMO, F
背景肢端肥大症患者血清胰岛素样生长因子-I（IGF-I）水平升高，常发生心肌肥大。在本研究中，我们研究是否IGF-I诱导肥大在培养的新生大鼠心肌细胞通过其特异性受体和是否IGF结合蛋白-3（IGFBP-3），这是一个主要的循环载体蛋白IGF-I，抑制IGF-I诱导的心脏肥大在体外。由于心脏肥大反应的特征在于诱导肌肉特异性基因的表达，因此通过北方印迹分析评价了IGF-I对肌球蛋白轻链-2（MLC-2）和肌钙蛋白I以及骨骼和心脏α-肌动蛋白亚型mRNA稳态水平的影响。IGF-I（10（-7）M）最早在60分钟时增加MLC-2和肌钙蛋白I的mRNA水平，6小时时达到最大水平，并维持长达24小时。IGF-I（10（-7）M）也增加骨骼α-肌动蛋白的转录，但不增加心脏α-肌动蛋白的转录。用IGF-I处理48小时后，通过形态测定法评价的细胞大小几乎加倍。IGF-I对蛋白质合成的诱导具有剂量依赖性（10（-10）至10（-7）M），在10（-8）M时观察到最大增加2.2倍。与IGF-I的肥大作用相反，生长激素既不影响蛋白质合成，也不影响肌肉特异性基因的表达。使用I-125-IGF-I的结合研究揭示了大鼠心肌细胞中存在IGF-I的特异性结合位点。IGFBP-3诱导IGF-I刺激的蛋白质合成的剂量依赖性抑制; IGFBP-3（10（-7）M）完全抑制IGF-I（10（-8）M）刺激的[H-3]亮氨酸摄取。IGFBP-3同样抑制IGF-I刺激的MLC-2和肌钙蛋白I的基因表达。这些结果表明，IGF-I直接导致心肌肥大，其作用可被IGFBP-3阻断。
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 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 a-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 I-125-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 [H-3]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.