A novel protective effect of erythropoietin in the infarcted heart
Cyrus J. Parsa, Akio Matsumoto, Jihee Kim, Ryan U. Riel, Laura S. Pascal, G. Brant Walton, Richard B. Thompson, Jason A. Petrofski, Brian H. Annex, Jonathan S. Stamler, Walter J. Koch
Cyrus J. Parsa, Akio Matsumoto, Jihee Kim, Ryan U. Riel, Laura S. Pascal, G. Brant Walton, Richard B. Thompson, Jason A. Petrofski, Brian H. Annex, Jonathan S. Stamler, Walter J. Koch
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Article Cardiology

A novel protective effect of erythropoietin in the infarcted heart

Abstract

Erythropoietin (EPO) has been shown to protect neurons from ischemic stroke, but can also increase thrombotic events and mortality rates in patients with ischemic heart disease. We reasoned that benefits of EPO might be offset by increases in hematocrit and evaluated the direct effects of EPO in the ischemic heart. We show that preconditioning with EPO protects H9c2 myoblasts in vitro and cardiomyocytes in vivo against ischemic injury. EPO treatment leads to significantly improved cardiac function following myocardial infarction. This protection is associated with mitigation of myocyte apoptosis, translating into more viable myocardium and less ventricular dysfunction. EPO-mediated myocyte survival appears to involve Akt activation. Importantly, cardioprotective effects of EPO were seen without an increase in hematocrit (eliminating oxygen delivery as an etiologic factor in myocyte survival and function), demonstrating that EPO can directly protect the ischemic and infarcted heart.

Authors

Cyrus J. Parsa, Akio Matsumoto, Jihee Kim, Ryan U. Riel, Laura S. Pascal, G. Brant Walton, Richard B. Thompson, Jason A. Petrofski, Brian H. Annex, Jonathan S. Stamler, Walter J. Koch

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Apoptotic cell death in H9c2 myoblasts exposed to oxidative stress and h...
Apoptotic cell death in H9c2 myoblasts exposed to oxidative stress and hypoxia. (a) The ratio of apoptotic cells to total adherent cells in the dish following oxidative stress (H2O2 exposure). Cells were treated with H2O2 (200 μM) following the treatment with EPO (0.4 or 10 U/ml, n = 8 each). Cells were stained with Hoechst 33258 dye, and nuclear morphology was revealed by fluorescent microscopy (described in Methods). Data shown are the mean ± SEM. *P < 0.05 versus untreated cells. (b) The ratio of apoptotic cells to total adherent cells in the dish after hypoxic injury. Cells were exposed to anoxia (12 hours) and percentage of nuclear fragmentation quantified under the following conditions: vehicle (control), DMSO (n = 4), white bars; wortmanin (n = 4), black bars; and PD98059 (n = 4), gray bars. Presence (8 U/ml) or absence of EPO is indicated by + and –, respectively. Cells were stained as above. *P < 0.05 versus vehicle-treated (DMSO), †P < 0.05 versus EPO alone. (c and d) Representative sample of H9c2 cells treated with H2O2 (200 μM) without EPO pretreatment (c) or with EPO (10 U/ml) for 24 hours (d). Arrows indicate fragmented nuclei under both conditions.