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

Introduction The cytokine cardiotrophin-1 (CT-1) is a member of the IL-6 family of cytokines acting through the heterodimeric complex LIFR␤:gp130 that becomes tyrosine phosphorylated by Janus kinases (Jaks). The Jaks activate multiple downstream signalling pathways, which involve signal transducers and activators of transcription (STATs), MAPKs, PI3-kinase and NF-␬B (Freed et al., 2005; Pennica et al., 1996). Several biological effects with vital importance on heart development and function have been attributed to CT-1. In embryonic and neonatal cardiomyocytes CT-1 has been demonstrated to mediate cell proliferation and support cell survival (Sheng et al., 1996). In ES cells CT-1 has been recently shown to stimulate cardiomyogenic differentiation and cell proliferation by a mechanism involving ROS as signalling molecules in Jak/STAT-, MAPK-and NF-␬B-mediated signal transduction cascades (Sauer et al., 2004). Besides its important function in embryonic and neonatal tissues CT-1 exerts a protective function in the adult heart by inducing cell hypertrophy through stimulation of sarcomere assembly in series with the subsequent increase in cardiomyocyte cell length (Wollert et al., 1996), and by preventing apoptosis in vitro and in vivo (Sheng et al., 1997). Furthermore, CT-1 has been shown to