A cordial affair - erythropoietin and cardioprotection.

Hypoxia and erythropoietin (EPO) were a couple from the very beginning. Hypoxia induces the production of EPO, which became the paradigm for oxygen-regulated gene expression [1]. Dissecting EPO gene regulation has lead to the discovery of the transcription factor complex hypoxia inducible factor-1 (HIF-1), the widespread “master regulator of O2 homeostasis” in the tissue, and the identification of cellular oxygen sensors in control of HIF-1 (reviewed by [2]). EPO as a erythropoietic hormone is mainly synthesized by the kidneys in the adult, and in the liver before birth [1]. However, EPO is also expressed in the brain, in the gonads and female reproductive tract, in the bone marrow, and in tumor cells [1] due to tissue specific transcription factors, e.g. WT1 [3], which are most likely integrated into oxygendependent regulation. It is now well recognized that EPO has a much broader range of action than its well-known role as an erythropoiesisstimulating hormone [4]. EPO inhibits apoptosis in neurons, endothelial smooth muscle cells, and cardiomyocytes, and EPO expression in organs other than the kidneys appears to act in a paracrine way [5]. While signaling of EPO through erythropoietin receptor (EPOR) activation in erythroid progenitors is well characterized, knowledge of the signal transduction in other EPO-responsive cells is still fragmentary. EPO-induced signaling in neurons was suggested to serve as a paradigm to better understand cardioprotection by EPO [5]. However, extensive studies of the signaling pathways responsible for neuroprotective effects have not provided a consensus whether activation of the classical EPOR alone is responsible for neuroprotection [6,7].