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Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13352 Berlin, Germany

Can erythropoietin improve skeletal myoblast engraftment in infarcted myocardium?

eComment: Dr. Chanseaume and colleagues are to be congratulated for testing a potentially important new treatment concept in a straightforward experimental model, and for not hesitating to report the apparently disappointing result [1]. In a way, the title of the paper seems overly pessimistic, since it is by no means clear that erythropoietin in general cannot improve skeletal myoblast engraftment. As the authors discussed in the paper, the systemic route of delivery is unlikely to achieve sufficient local drug concentrations to induce a relevant amount of angiogenesis within the given time frame. Moreover, EPO is unlikely to reach one of its most important targets, the myoblasts themselves. A few years ago, Ogilvie et al. performed a very comprehensive assessment of the EPO effects on myoblasts (both C2C12 cells and primary murine satellite cells), and found that EPO not only stimulates myoblast proliferation in vitro but also inhibits their differentiation in myotubes [2]. The implications these findings should have on experimental design are self-evident. Since the date of submission of Dr. Chanseaume's manuscript, a number of other related papers have been published. Of note, Miki et al. reported that in the infarcted myocardium the typical cardioprotective EPO signalling cascade involving JAK-2, PI3K and Akt is disrupted, which implies that the chronically ischemic myocardium might be intrinsically less responsive to EPO [3]. Regarding the EPO effects on angiogenesis, Hirata et al. confirmed the notion of a narrow time window for EPO-induced myocardial revascularization in a clinically relevant dog model [4]. Nakano et al. very recently demonstrated a link between vascular EPO receptor in ischemic tissue, VEGF secretion, and recruitment of endothelial progenitor cells [5]; the key features of the EPO receptor were summarized in an accompanying editorial [6].

Taken together, the biology and therapeutic potential of EPO in ischemic heart disease is very complex. Although it was not effective in the specific experimental protocol Dr. Chanseaume and his colleagues used, EPO still holds promise for enhancing the efficacy of myocardial cell therapy.

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1. Chanséaume S, Azarnoush K, Maurel A, Bellamy V, Peyrard S, Bruneval P, Hagege AA, Menasché P. Can erythropoietin improve skeletal myoblast engraftment in infarcted myocardium? Interact CardioVasc Thorac Surg 2007; 6:293–297.[Abstract/Free Full Text]
2. Ogilvie M, Yu X, Nicolas-Metral V, Pulido SM, Liu C, Ruegg UT, Noguchi CT. Erythropoietin stimulates proliferation and interferes with differentiation of myoblasts. J Biol Chem 275;39754–39761.
3. Miki T, Miura T, Yano T, Takahashi A, Sakamoto J, Tanno M, Kobayashi H, Ikeda Y, Nishihara M, Naitoh K, Ohori K, Shimamoto K. Alteration in erythropoietin-induced cardioprotective signaling by postinfarct ventricular remodeling. J Pharmacol Exp Ther 2006; 317:68–75.[Abstract/Free Full Text]
4. Hirata A, Minamino T, Asanuma H, Fujita M, Wakeno M, Myoishi M, Tsukamoto O, Okada KI, Koyama H, Komamura K, Takashima S, Shinozaki Y, Mori H, Shiraga M, Kitakaze M, Hori M. Erythropoietin enhances neovascularization of ischemic myocardium and improves left ventricular dysfunction after myocardial infarction in dogs. J Am Coll Cardiol 2006; 48:176–184.[Abstract/Free Full Text]
5. Nakano M, Satoh K, Fukumoto Y, Ito Y, Kagaya Y, Ishii N, Sugamura K, Shimokawa H. Important role of erythropoietin receptor to promote VEGF expression and angiogenesis in peripheral ischemia in mice. Circ Res 2007; 100:662–669.[Abstract/Free Full Text]

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