Erythropoietin (EPO), well known for its role in stimulation of erythropoiesis, has recently been shown to have a dramatic neuroprotective effect in animal models of cerebral ischemia, mechanical trauma of the nervous system, and excitotoxins, mainly by reducing apoptosis. We studied the effect of single systemic administration of recombinant human EPO (rhEPO) on left ventricular (LV) size and function in rats during 8 weeks after the induction of a myocardial infarction (MI) by permanent ligation of the left descending coronary artery. We found that an i.p. injection of 3,000 units͞kg of rhEPO immediately after the coronary artery ligation resulted, 24 h later, in a 50% reduction of apoptosis in the myocardial area at risk. Eight weeks after the induction of MI, rats treated with rhEPO had an infarct size 15-25% of the size of that in untreated animals. The reduction in myocardial damage was accompanied by reductions in LV size and functional decline as measured by repeated echocardiography. Thus, a single dose of rhEPO administered around the time of acute, sustained coronary insufficiency merits consideration with respect to its therapeutic potential to limit the extent of resultant MI and contractile dysfunction. E rythropoietin (EPO), a cytokine produced by the adult kidney, is a well known hematopoietic factor. EPO receptors (EPO-Rs) are expressed in adult bone marrow and spleen and are activated by hypoxia (1). Whether EPO-Rs are present in nonhematopoietic tissues is less certain. The predominant opinion is that the expression of EPO-Rs in nonhematopoietic tissues is limited to the fetal stage of development (2). Although some studies failed to detect EPO-R transcripts in the brain, kidney, liver, or heart of adult mice (3), others have reported an intensive immunoreactivity for EPO-Rs in many medium and large neurons of adult rat brain (4). Moreover, a weak EPO-R immunoreactivity of human brain was amplified by hypoxia (5). Recently, EPO-Rs have also been identified in the adult retina of mice (6). Although EPO-Rs have not been identified in adult hearts, their presence during embryogenesis is critical for cardiac development (7).Recombinant human EPO (rhEPO) is widely used for the treatment of anemia occurring in the context of surgery, cancer, HIV, kidney failure, etc. (8). Recently, rhEPO has been shown to have a dramatic neuroprotective effect in animal models of cerebral ischemia and mechanical trauma of the nervous system, and in response to excitotoxins. A single intracerebroventricular injection and, more importantly, systemic administration of rhEPO have resulted in a 50-75% reduction in brain injury induced by the focal ischemia (4). A reduction of apoptosis is a mechanism involved in this neuroprotective effect of rhEPO (9, 10).We hypothesized that the protective effect of systemic rhEPO administration that resulted in improvement of brain cell survival after cerebral ischemia would also occur in the ischemic heart model. Specifically, we studied the effect of a single systemic administration...

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...

Rheumatoid arthritis is a joint-specific autoimmune inflammatory disease of unknown etiology. The K/BxN mouse is a model of rheumatoid arthritis that is thought to be mainly due to autoantibody-mediated inflammatory responses. We showed previously that homeostatic proliferation of autoreactive CD4+ T cells is required for disease initiation in the K/BxN mice. In this study, we show that the homeostatically proliferating CD4+CD25− T cells produce IL-21. We generated IL-21R-deficient (IL-21R−/−) K/BxN mice and found that these mice were completely refractory to the development of spontaneous arthritis. They contained fewer CD4+ T cells with a reduced proportion of homeostatically proliferating cells, fewer follicular Th cells, and, surprisingly, more Th17 cells than their control counterparts. They also failed to develop IgG1+ memory B cells and autoantigen-specific IgG1 Ab-secreting cells. IL-21 induced expression of receptor activator of NF-κB ligand (RANKL) a regulator of osteoclastogenesis, and few RANKL-expressing infiltrates were found in the synovia of IL-21R−/− K/BxN mice. Thus, our results demonstrate that IL-21 forms a positive feedback autocrine loop involving homeostatically activated CD4+ cells and that it plays an essential role in the development of autoimmune arthritis by mechanisms dependent on follicular Th cell development, autoreactive B cell maturation, and RANKL induction but independent of Th17 cell function. Consistent with this, in vivo administration of soluble the IL-21R-Fc fusion protein delayed the onset and progression of arthritis. Our findings suggest that effective targeting of IL-21-mediated processes may be useful in treating autoimmune arthritis.