Ito H, Hiroe M, Hirata Y, Tsujino M, Adachi S, Shichiri M, Koike A, Nogami A, Marumo F
Second Department of Internal Medicine, Tokyo Medical and Dental University, Japan.
Circulation. 1993 May;87(5):1715-21. doi: 10.1161/01.cir.87.5.1715.
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.
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.
These results suggest that IGF-I directly causes cardiac hypertrophy and that its effect can be blocked by IGFBP-3.
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。
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。
这些结果表明IGF-I直接导致心脏肥大，且其作用可被IGFBP-3阻断。
