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

Abstract

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 toxininduced 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 g/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 CEPOand EPO-treated rats was half of that in untreated coronaryligated 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.Erythropoietin (EPO) is a well known hematopoietic cytokine produced by the kidney in response to hypoxia (Youssoufian et al., 1993). Recombinant human EPO (rhEPO) is widely used to treat the anemia related to surgery, cancer, and kidney failure (Jelkmann, 1994). However, EPO possesses much broader salutary effects than merely stimulation of red blood cell production. EPO receptors, originally thought to be confined only to hematopoietic tissue in adults, were also found in other tissues, for example, neural tissue (for review, see Masuda et al., 1999). Many recent studies have demonstrated the neuroprotective effects of rhEPO in different animal models (Sadamoto et al., 1998;Bernaudin et al., 1999;Brines et al., 2000) and in a phase II clinical trial in cerebral ischemia (Ehrenreich et al., 2002).In several recent studies, the effects of systemic administration of rhEPO have been extended to include cardioprotection from ischemia. The antiapoptotic effects of rhEPO on cardiomyocytes have been reported in tissue culture and in vivo animal models of ischemia-reperfusion injury (for review, see Smith et al., 2003;Bogoyevitch, 2004). The recent discovery of EPO receptors in cardiomyocytes of adult rat solidified these findings (Wright et al., 2004).In a rat model of myocardi...

Low‐dose erythropoietin improves cardiac function in experimental heart failure without increasing haematocrit

“…The possibility of separating the erythropoietic and tissue protective effects of EPO could be explained through interaction with different receptors in the bone marrow and in "peripheral" tissues. Two independent studies have demonstrated that these non-erythropoietic EPO's retain their acute cardioprotective potential [31,32]. It is however uncertain whether these new EPO's will also improve cardiac function in CHF.…”

Neurorestorative treatment of stroke: Cell and pharmacological approaches

“…Recently introduced, carbamylated erythropoietin (CEPO) does not stimulate erythropoiesis but retains the antiapoptotic and neuroprotective effects of EPO. 71,72 Treatment with CEPO 24 hours after stroke reduces perifocal microglial activation and white matter damage, and significantly improves functional outcome after stroke. 73 Mechanisms of EPO-induced neurorestoration.…”

Erythropoietin and Oxidative Stress

“…EPO administration in patients also can significantly increase plasma levels of EPO well above this range of 1.0 ng/ml that has been associated with potential EPO cellular protection in patients with cardiac or renal disease (Mason-Garcia, et al, 1990, Namiuchi, et al, 2005, suggesting that the effects of EPO observed during in vitro studies may parallel the cellular processes altered by EPO in patients with DM (Bierer, et al, 2006). Furthermore, EPO can block apoptotic DNA degradation in ECs during elevated glucose similar to other models of oxidative stress in cardiac and vascular cell models (Avasarala and Konduru, 2005, Chong, et al, 2002b, Moon, et al, 2006. The preservation of cellular energy reserves is dependent upon the maintenance of mitochondrial integrity during DM (Newsholme, et al, 2007).…”