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...

SummaryThe citric acid cycle (CAC) metabolite fumarate has been proposed to be cardioprotective; however, its mechanisms of action remain to be determined. To augment cardiac fumarate levels and to assess fumarate's cardioprotective properties, we generated fumarate hydratase (Fh1) cardiac knockout (KO) mice. These fumarate-replete hearts were robustly protected from ischemia-reperfusion injury (I/R). To compensate for the loss of Fh1 activity, KO hearts maintain ATP levels in part by channeling amino acids into the CAC. In addition, by stabilizing the transcriptional regulator Nrf2, Fh1 KO hearts upregulate protective antioxidant response element genes. Supporting the importance of the latter mechanism, clinically relevant doses of dimethylfumarate upregulated Nrf2 and its target genes, hence protecting control hearts, but failed to similarly protect Nrf2-KO hearts in an in vivo model of myocardial infarction. We propose that clinically established fumarate derivatives activate the Nrf2 pathway and are readily testable cytoprotective agents.

Background-Intermittent fasting (IF), a dietary regimen in which food is available only every other day, increases the life span and reduces the incidence of age-associated diseases in rodents. We have reported neuroprotective effects of IF against ischemic injury of the brain. In this study, we examined the effects of IF on ischemic injury of the heart in rats. Methods and Results-After 3 months of IF or regular every-day feeding (control) diets started in 2-month-old rats, myocardial infarction (MI) was induced by coronary artery ligation. Twenty-four hours after MI, its size in the IF group was 2-fold smaller, the number of apoptotic myocytes in the area at risk was 4-fold less, and the inflammatory response was significantly reduced compared with the control diet group. Serial echocardiography revealed that during 10 weeks after MI (with continuation of the IF regimen), the left ventricular (LV) remodeling and MI expansion that were observed in the control diet group were absent in the IF group. In a subgroup of animals with similar MI size at 1 week after MI, further observation revealed less remodeling, better LV function, and no MI expansion in the IF group compared with the control group. Conclusions-IF protects the heart from ischemic injury and attenuates post-MI cardiac remodeling, likely via antiapoptotic and antiinflammatory mechanisms.