Cardioprotective Effects of Erythropoietin in the Reperfused Ischemic Heart

Abstract

Erythropoietin has recently been shown to have effects beyond hematopoiesis such as prevention of neuronal and cardiac apoptosis secondary to ischemia. In this study, we evaluated the in vivo protective potential of erythropoietin in the reperfused rabbit heart following ventricular ischemia. We show that "preconditioning" with erythropoietin activates cell survival pathways in myocardial tissue in vivo and adult rabbit cardiac fibroblasts in vitro. These pathways, activated by erythropoietin in both whole hearts and cardiac fibroblasts, are also activated acutely by ischemia/reperfusion injury. Moreover, in vivo studies indicate that erythropoietin treatment either prior to or during ischemia significantly enhances cardiac function and recovery, including left ventricular contractility, following myocardial ischemia/reperfusion. Our data indicate that a contributing in vivo cellular mechanism of this protection is mitigation of myocardial cell apoptosis. This results in decreased infarct size as evidenced by area at risk studies following in vivo ischemia/reperfusion injury, translating into more viable myocardium and less ventricular dysfunction. Therefore, erythropoietin treatment may offer novel protection against ischemic heart disease and may act, at least in part, by direct action on cardiac fibroblasts and myocytes to alter survival and ventricular remodeling.

Erythropoietin improves functional and histological recovery of traumatized skeletal muscle tissue

“…Although there are extralaminally located muscle-derived stem cells known to give rise to determine myoblasts and to differentiate to myotubes, 5 the majority of these interstitial cells is supposed to be fibroblasts, which might also benefit from the antiapoptotic and/or mitogenic action of EPO. Similarly as supposed for cardiac fibroblasts, 41 the response of these interstitial cells to EPO seems to represent an important process contributing to the pathobiology of muscle tissue repair. In support of this view, the maturation of scar tissue, that is, the condensation from large granulation tissue toward small connective tissue mass, was found more efficient in muscle tissue of EPO-treated animals, as indicated by the markedly lower amount of Sirius Redstained collagen and by the significantly higher values of mechanical contraction forces at 42 days after trauma.…”

A Novel Role for Vascular Endothelial Growth Factor as an Autocrine Survival Factor for Embryonic Stem Cells during Hypoxia

“…Indeed, a survival activity has been documented for bFGF, PDGF-B, VEGF, nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 and erythropoietin for hypoxic neurons (15,(35)(36)(37)(38)(39)(40)(41), acidic fibroblast growth factor, IGF-I and erythropoietin for hypoxic myocardial cells (42)(43)(44)(45)(46), VEGF for hypoxic chondrocytes (47), or hepatocyte growth factor and erythropoietin for hypoxic renal cells (48,49). Growth factors may also protect cells against apoptosis in response to other stimuli, as exemplified by the ability of erythropoietin, c-kit ligand, or interleukin-3 to block p53-mediated apoptosis of hematopoietic cell lines (50 -52) by the protective effect of IGF-I or EGF on epithelial cells or lymphocytes against Fas-induced apoptosis (53)(54)(55) or by the inhibition by IGF-I of glutamateinduced apoptosis of oligodendrocyte progenitors (56).…”

Epo and Non-hematopoietic Cells: What Do We Know?

“…Epo receptors and functional responses to Epo were shown in isolated cardiomyocytes (141,(143)(144)(145)(146) coronary endothelial cells (83, 147) and fibroblasts (148). The cardiac EpoR was shown to respond equally efficiently to Epo, carbomylated Epo (CEPO), and ARA-290 (141,149,150), a synthetic Epo mimetic comprised only of helix B part of the cytokine.…”