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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 23, 2005; DOI: 10.1124/jpet.105.094854

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Received for publication August 30, 2005.
Revised November 21, 2005.
Accepted for publication November 21, 2005.

Erythropoietin, modified to not stimulate red blood cell production , retains its cardioprotective properties

Chanil Moon 1, Melissa Krawczyk 1, Doojin Paik 2, Thomas Coleman 3, Michael Brines 4, Magdalena Juhaszova 1, Steven Sollott 1, Edward G. Lakatta 1, Mark I. Talan 1*

1 National Institute on Aging 2 Hanyang University, Korea 3 Kenneth S. Warren Institute 4 Ketteth S. Warren Institute

* Address correspondence to: E-mail: talanm{at}grc.nia.nih.gov

Abstract

Background. Erythropoietin (EPO), a hematopoietic cytokine, possesses strong antiapoptotic, tissue-protective properties. For clinical applications it is desirable to separate the hematopoietic and tissue-protective properties. Recently introduced carbamylated erythropoietin (CEPO) does not stimulate the erythropoiesis, but retains the antiapoptotic and neuroprotective effects. We tested the ability of CEPO to protect cardiac tissue from toxin-induced and oxidative stress in vitro and ischemic damage in vivo and compared these effects with the effects of EPO. Methods and Results. CEPO reduced by 50% the extent of staurosporine-induced apoptosis in isolated rat's cardiomyocytes, and increased by 25% the Reactive Oxygen Species threshold for induction of the mitochondrial permeability transition. In an experimental model of myocardial infarction induced by permanent ligation of a coronary artery in rats, similarly to EPO, a single bolus injection of 30µg/kg-bw of CEPO immediately after coronary ligation reduced apoptosis in the myocardial area at risk, examined 24 hrs later, by 50%. Left ventricular remodeling (ventricular dilation) and functional decline (fall in ejection fraction) assessed by repeated echocardiography were significantly and similarly attenuated in CEPO- and EPO-treated rats. Four weeks after coronary ligation, the MI size in CEPO- and EPO-treated rats was half of that in untreated coronary ligated animals. Unlike EPO, CEPO had no effect on hematocrit. Conclusions. The antiapoptotic cardioprotective effects of CEPO, shown by its ability to limit both post-MI left ventricular remodeling and the extent of the myocardial scar in the model of permanent coronary artery ligation in rats, demonstrate comparable potency to that of native (non-modified) EPO.


Key words: LV dilation, LV remodeling, Myocardial infarction, apoptosis, cardioprotection, erythropoietin


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