Hypoxia changes the expression of the epidermal growth factor (EGF) system in human hearts and cultured cardiomyocytes.
Hypoxia changes the expression of the epidermal growth factor (EGF) system in human hearts and cultured cardiomyocytes.
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缺氧改变了人心脏和培养的心肌细胞中表皮生长因子（EGF）系统的表达。
DOI：
10.1371/journal.pone.0040243
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Sorensen BS
中科院分区：
文献类型：
--
作者：
Munk M;Memon AA;Goetze JP;Nielsen LB;Nexo E;Sorensen BS
表皮生长因子（EGF）受体HER 2和HER 4以及配体HB-EGF和NRG 1对心脏发育至关重要。本研究的目的是研究EGF系统在心脏缺氧中的作用。我们通过真实的时间PCR检测了在冠状动脉搭桥手术期间从人心脏分离的成对常氧和缺氧活检组织中EGF系统的4种受体和12种配体的mRNA表达。与常氧活检相比，缺氧样本显示HER 2（P = 0.0005）和NRG 1（α（P = 0.02）和β（P = 0.03）亚型）下调。 而HB-EGF（P = 0.0008）、NRG 2 β（P = 0.01）和EGFR（P = 0.02）表达上调。 由于HER 2对心脏发育至关重要，我们发现其表达在缺氧条件下降低，因此我们研究了曲妥珠单抗（20 nM）治疗对缺氧HL-1心肌细胞中HER 2抑制的影响。这导致心肌细胞增殖的抑制，但有趣的是仅在缺氧细胞中。用HB-EGF（10 nM）而不是NRG-1（5 ng/ml）共处理HL-1细胞可使心肌细胞免于HER 2抑制。暴露于缺氧的HL-1心肌细胞显示活化MAPK的核转位，并且该下游信号分子的活性通过HER 2抑制（20 nM曲妥珠单抗）降低，并通过HB-EGF（10 nM）重建。人体心脏缺氧会改变EGF系统的表达。在培养的心肌细胞中模拟人类心脏中观察到的HER 2下调抑制了它们在缺氧条件下的增殖。有趣的是，HB-EGF在缺氧的人类心脏中被诱导，并在体外模型中拯救缺氧的心肌细胞免受HER 2抑制的影响。这些结果对缺血性心脏病患者未来的治疗策略具有启示意义。
The epidermal growth factor (EGF) receptors HER2 and HER4 and the ligands HB-EGF and NRG1 are crucial for heart development. The purpose of our study was to investigate the role of the complete EGF system in relation to hypoxia of the heart. We examined the mRNA expression by real time PCR of the 4 receptors and 12 ligands from the EGF-system in paired normoxic and hypoxic biopsies isolated from human hearts during coronary artery bypass operation. Compared to normoxic biopsies, hypoxic samples showed down-regulation of HER2 (P = 0.0005) and NRG1 (both α (P = 0.02) and β (P = 0.03) isoforms). In contrast, HB-EGF (P = 0.0008), NRG2β (P = 0.01) and EGFR (P = 0.02) were up-regulated. As HER2 is essential for heart development and we find its expression reduced under hypoxia we investigated the effect of HER2 inhibition in hypoxic HL-1 cardiomyocytes by treatment with trastuzumab (20 nM). This resulted in inhibition of cardiomyocyte proliferation, but interestingly only in hypoxic cells. Co-treatment of HL-1 cells with HB-EGF (10 nM) but not with NRG-1 (5 ng/ml) rescued the cardiomyocytes from HER2 inhibition. HL-1 cardiomyocytes exposed to hypoxia revealed nuclear translocation of activated MAPK and the activity of this downstream signaling molecule was decreased by HER2 inhibition (20 nM trastuzumab), and re-established by HB-EGF (10 nM). Hypoxia in the human heart alters the expression of the EGF system. Mimicking the HER2 down-regulation seen in the human heart in cultured cardiomyocytes inhibited their proliferation under hypoxic conditions. Interestingly, HB-EGF is induced in the hypoxic human hearts, and rescues hypoxic cardiomyocytes from the effect of HER2 inhibition in the in vitro model. The results have implications for future treatment strategies of patients with ischemic heart disease.
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影响因子：
45.3
作者：
Suter, Thomas M.;Procter, Marion;Piccart-Gebhart, Martine J.
通讯作者：
Piccart-Gebhart, Martine J.
影响因子：
64.5
作者：
Bersell, Kevin;Arab, Shima;Kuehn, Bernhard
通讯作者：
Kuehn, Bernhard
影响因子：
64.8
作者：
Dimmeler, S;Fleming, I;Zeiher, AM
通讯作者：
Zeiher, AM
影响因子：
64.8
作者：
GASSMANN, M;CASAGRANDA, F;LEMKE, G
通讯作者：
LEMKE, G
DOI：
10.1161/01.atv.0000030199.06252.26
发表时间：
2002-09-01
影响因子：
8.7
作者：
Nielsen, LB;Perko, M;Andersen, CB
通讯作者：
Andersen, CB