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CARDIOVASCULAR

Erythropoietin, Modified to Not Stimulate Red Blood Cell Production, Retains Its Cardioprotective Properties

Laboratory of Cardiovascular Sciences, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland (C.M., M.K., M.J., S.J.S., E.G.L., M.I.T.); Department of Anatomy and Cell Biology, Hanyang University, Seoul, Korea (D.P.); and Kenneth S. Warren Institute and Warren Pharmaceuticals, Ossining, New York (T.C., M.B.)

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. CEPO reduced by 50% the extent of staurosporine-induced apoptosis in isolated rats' 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 30 µg/kg b.wt. of CEPO immediately after coronary ligation reduced apoptosis in the myocardial area at risk, examined 24 h 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 myocardial infarction (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. 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 (nonmodified) EPO.

Address correspondence to: Dr. Mark Talan, Senior Investigator, Head, Cardiovascular Gene Therapy Unit, Laboratory of Cardiovascular Sciences, Intramural Research Program, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, MD 21224-6825. E-mail talanm{at}grc.nia.nih.gov

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