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Growth hormone signalling and apoptosis in neonatal rat cardiomyocytes

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Abstract

Growth hormone (GH) has been reported to be useful to treat heart failure. To elucidate whether GH has direct beneficial effects on the heart, we examined effects of GH on oxidative stress-induced apoptosis in cardiac myocytes. TUNEL staining and DNA ladder analysis revealed that hydrogen peroxide (H2O2)-induced apoptosis of cardiomyocytes was significantly suppressed by the pretreatment with GH. GH strongly activated extracellular signal-regulated kinases (ERKs) in cardiac myocytes and the cardioprotective effect of GH was abolished by inhibition of ERKs. Overexpression of dominant negative mutant Ras suppressed GH-stimulated ERK activation. Overexpression of Csk that inactivates Src family tyrosine kinases also inhibited ERK activation evoked by GH. A broad-spectrum inhibitor of protein tyrosine kinases (PTKs), genistein, strongly suppressed GH-induced ERK activation and the cardioprotective effect of GH against apoptotic cell death. GH induced tyrosine phosphorylation of EGF receptor and JAK2 in cardiac myocytes, and an EGF receptor inhibitor tyrphostin AG1478 and a JAK2 inhibitor tyrphostin B42 completely inhibited GH-induced ERK activation. Tyrphostin B42 also suppressed the phosphorylation of EGF receptor stimulated by GH. These findings suggest that GH has a direct protective effect on cardiac myocytes against apoptosis and that the effect of GH is attributed at least in part to the activation of ERKs through Ras and PTKs including JAK2, Src, and EGF receptor tyrosine kinase.

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo

    Yaping Gu, Ryuichi Aikawa, Doubun Hayashi, Sumiyo Kudoh, Toshimasa Yamauchi, Hiroki Uozumi, Weidong Zhu, Takashi Kadowaki & Yoshio Yazaki

  2. Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan

    Yunzeng Zou & Issei Komuro

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  1. Yaping Gu
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  2. Yunzeng Zou
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Correspondence to Issei Komuro.

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Gu, Y., Zou, Y., Aikawa, R. et al. Growth hormone signalling and apoptosis in neonatal rat cardiomyocytes. Mol Cell Biochem 223, 35–46 (2001). https://doi.org/10.1023/A:1017941625858

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