Iwabu Akihiro, Murakami Takashi, Kusachi Shozo, Nakamura Keigo, Takemoto Syunji, Komatsubara Issei, Sezaki Satoshi, Hayashi Junichi, Ninomiya Yoshifumi, Tsuji Takao
Department of Internal Medicine I, Okayama University Medical School, Japan.
Basic Res Cardiol. 2002 May;97(3):214-22. doi: 10.1007/s003950200014.
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is mitogenic and chemotactic for many cell types. HB-EGF is induced in pathological states which require cell mitogenesis and proliferation, including angiogenesis, and has been reported to interact functionally with basic fibroblast growth factor (bFGF). To test our hypothesis that HB-EGF mRNA expression is increased in myocardial infarction, we used Northern hybridization in rats to investigate the expression of HB-EGF and EGF receptor mRNAs expression in the infarct zone compared to the expression of bFGF and FGF receptor mRNAs. We also performed in situ hybridization to identify the cells responsible for HB-EGF mRNA production. HB-EGF mRNA rapidly increased after ligation (mean +/- SE, 5.6+/-0.23-fold increase at 6 hours compared to the preligation heart levels) and reached a maximum level (9.1+/-0.42-fold increase) around 12 hours. HB-EGF mRNA then gradually decreased on day 1 (5.8+/-1.0-fold increase), day 2 (3.2+/-0.94-fold increase) and day 3 (1.9+/-0.33-fold increase) after ligation. Parallel changes in bFGF mRNA expression were observed (6, 12 hours, days 1, 2 and 3; 3.6+/-0.42-, 5.3+/-0.12-, 2.3+/-0.12-, 1.7+/-0.03- and 0.95+/-0.03-fold increase, respectively). EGF receptor (ErbB-1) mRNA was gradually increased on day 2 (2.4+/-0.53-fold increase), day 7(4.0+/-0.61-fold increase) and day 14 (7.0+/-0.61-fold increase). Similarly, FGF receptor (FGF receptor-1) mRNA was gradually increased (days 2,7 and 14; 1.3+/-0.13-, 1.5+/-0.17- and 2.3+/-0.15-fold increase, respectively). Reperfusion after a 2-hour ligation (too late to salvage myocytes) enhanced HB-EGF (12 hours, 16.8+/-1.8-fold increase) and bFGF (12 hours, 10.4+/-1.1-fold increase) mRNA expression. The cells responsible for the increased production of HB-EGF mRNA were shown by in situ hybridization to be surviving myocytes located in the infarct peripheral zone around infarct necrotizing tissue. In conclusion, our results demonstrated a rapid increase in HB-EGF mRNA expression concomitant with an increase in bFGF mRNA expression, suggesting that HB-EGF and bFGF might play some role in the course of pathological changes in the infarct in the early inflammatory phase. Reperfusion at times too late to salvage myocytes accelerated sequential changes in the expression of both HB-EGF and bFGF mRNAs.
肝素结合表皮生长因子样生长因子（HB-EGF）对多种细胞类型具有促有丝分裂和趋化作用。HB-EGF在需要细胞有丝分裂和增殖的病理状态下被诱导产生，包括血管生成，并且据报道它能与碱性成纤维细胞生长因子（bFGF）发生功能性相互作用。为了验证我们的假设，即心肌梗死时HB-EGF mRNA表达增加，我们在大鼠中使用Northern杂交技术，研究梗死区域中HB-EGF和表皮生长因子受体（EGF受体）mRNA的表达，并与bFGF和FGF受体mRNA的表达进行比较。我们还进行了原位杂交，以确定产生HB-EGF mRNA的细胞。结扎后HB-EGF mRNA迅速增加（平均±标准误，与结扎前心脏水平相比，6小时时增加5.6±0.23倍），并在12小时左右达到最高水平（增加9.1±0.42倍）。然后，在结扎后的第1天（增加5.8±1.0倍）、第2天（增加3.2±0.94倍）和第3天（增加1.9±0.33倍），HB-EGF mRNA逐渐下降。观察到bFGF mRNA表达有平行变化（在6小时、12小时、第1天、第2天和第3天；分别增加3.6±0.42倍、5.3±0.12倍、2.3±0.12倍、1.7±0.03倍和0.95±0.03倍）。EGF受体（ErbB-1）mRNA在第2天（增加2.4±0.53倍）、第7天（增加4.0±0.61倍）和第14天（增加7.0±0.61倍）逐渐增加。同样，FGF受体（FGF受体-1）mRNA也逐渐增加（在第2天、第7天和第14天；分别增加1.3±0.13倍、1.5±0.17倍和2.3±0.15倍）。结扎2小时后再灌注（此时挽救心肌细胞已为时过晚）增强了HB-EGF（12小时时，增加16.8±1.8倍）和bFGF（12小时时，增加10.4±1.1倍）mRNA的表达。原位杂交显示，产生HB-EGF mRNA增加的细胞是位于梗死坏死组织周围梗死周边区域的存活心肌细胞。总之，我们的结果表明，HB-EGF mRNA表达迅速增加，同时bFGF mRNA表达也增加，这表明HB-EGF和bFGF可能在梗死早期炎症阶段的病理变化过程中发挥一定作用。在挽救心肌细胞为时过晚时进行再灌注加速了HB-EGF和bFGF mRNA表达的相继变化。
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