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First published online 28 February 2006
doi: 10.1242/jcs.02798

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Regulation of cardiotrophin-1 expression in mouse embryonic stem cells by HIF-1 and intracellular reactive oxygen species

¹ Department of Physiology, University of Giessen, 35392 Giessen, Germany
² GKSS Research Institute, Department of Cell Biology, 14513 Teltow, Germany
³ Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, and Zurich Center for Integrative Human Physiology (ZIHP), 8057 Zurich, Switzerland

^* Author for correspondence (e-mail: heinrich.sauer{at}physiologie.med.uni-giessen.de)

Accepted 15 November 2005

Cardiomyogenesis in differentiating mouse embryonic stem (ES) cells is promoted by cardiotrophin-1 (CT-1), a member of the IL-6 interleukin superfamily that acts through the tall gp130 cytokine receptor. We show that prooxidants (menadione, hydrogen peroxide) as well as chemical (CoCl₂) and physiological (1% O₂) hypoxia increased CT-1 as well as HIF-1 protein and mRNA expression in embryoid bodies, indicating that CT-1 expression is regulated by reactive oxygen species (ROS) and hypoxia. Treatment with either prooxidants or chemical hypoxia increased gp130 phosphorylation and protein expression of NADPH oxidase subunits p22-phox, p47-phox, p67-phox, as well as Nox1 and Nox4 mRNA. Consequently, inhibition of NADPH oxidase activity by diphenylen iodonium chloride (DPI) and apocynin abolished prooxidant- and chemical hypoxia-induced upregulation of CT-1. Prooxidants and chemical hypoxia activated ERK1,2, JNK and p38 as well as PI3-kinase. The proxidant- and CoCl₂-mediated upregulation of CT-1 was significantly inhibited in the presence of the ERK1,2 antagonist UO126, the JNK antagonist SP600125, the p38 antagonist SKF86002, the PI3-kinase antagonist LY294002, the Jak-2 antagonist AG490 as well as in the presence of free radical scavengers. Moreover, developing embryoid bodies derived from HIF-1^-/- ES cells lack cardiomyogenesis, and prooxidants as well as chemical hypoxia failed to upregulate CT-1 expression. Our results demonstrate that CT-1 expression in ES cells is regulated by ROS and HIF-1 and imply a crucial role of CT-1 in the survival and proliferation of ES-cell-derived cardiac cells.

Key words: Embryonic stem cells, cardiotrophin-1, reactive oxygen species, hypoxia-inducible factor-1, cardiomyogenesis, embryoid body

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