胰岛素样生长因子-I在培养的大鼠心肌细胞中诱导肥大，并增强肌肉特异性基因的表达。

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

作者信息

Ito H, Hiroe M, Hirata Y, Tsujino M, Adachi S, Shichiri M, Koike A, Nogami A, Marumo F

机构信息

Second Department of Internal Medicine, Tokyo Medical and Dental University, Japan.

出版信息

Circulation. 1993 May;87(5):1715-21. doi: 10.1161/01.cir.87.5.1715.

DOI:10.1161/01.cir.87.5.1715

PMID:7683979

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.

摘要

背景

肢端肥大症患者常出现心脏肥大，此类患者血清胰岛素样生长因子-I（IGF-I）水平升高。在本研究中，我们检测了IGF-I是否通过其特异性受体诱导培养的新生大鼠心肌细胞肥大，以及IGF结合蛋白-3（IGFBP-3）作为IGF-I的主要循环载体蛋白是否在体外抑制IGF-I诱导的心脏肥大。

方法与结果

由于心脏肥大的反应特征是肌肉特异性基因表达的诱导，通过Northern印迹分析评估IGF-I对肌球蛋白轻链-2（MLC-2）、肌钙蛋白I以及骨骼肌和心肌α-肌动蛋白异构体mRNA稳态水平的影响。IGF-I（10⁻⁷M）最早在60分钟时增加MLC-2和肌钙蛋白I的mRNA水平，6小时时达到最高水平，并持续长达24小时。IGF-I（10⁻⁷M）还增加骨骼肌α-肌动蛋白的转录本，但不增加心肌α-肌动蛋白的转录本。经形态计量学评估，用IGF-I处理48小时后细胞大小几乎翻倍。IGF-I诱导的蛋白质合成呈剂量依赖性（10⁻¹⁰至10⁻⁷M），在10⁻⁸M时最大增加2.2倍。与IGF-I的肥大效应相反，生长激素对蛋白质合成和肌肉特异性基因的表达均无影响。使用¹²⁵I-IGF-I的结合研究显示大鼠心肌细胞中存在IGF-I的特异性结合位点。IGFBP-3诱导对IGF-I刺激的蛋白质合成的剂量依赖性抑制；IGFBP-3（10⁻⁷M）完全抑制IGF-I（10⁻⁸M）刺激的[³H]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。