Erythropoietin (EPO) stimulates erythropoiesis through binding to and
activation of homodimeric receptors, comprised of two ~59 kDa transmembrane
proteins (EPO-R). Preclinical studies purported pleiotropic cytoprotective roles for the
EPO/EPO-R system in tissues and organs, and the potential benefits of erythropoiesisstimulating
agents (ESAs) for cardiovascular diseases are a focus of current research.
This article summarizes putative actions of ESAs in the cardiovascular system, with
emphasis on the human responses. The potential for EPO-mediated mobilization of
stem cells into the blood stream has attracted wide interest because of the possibility
that ESAs may promote the neovascularization of ischemic tissues. Supporting the
possibility, EPO-R mRNA is detectable in vascular endothelium, and EPO has been
reported to stimulate angiogenesis in some preclinical models. However, in most such
studies very high concentrations of EPO were applied. Moreover, recent well-designed
studies have failed to show direct effects of ESAs on endothelial cells. By use of a
specific anti-EPO-R antibody very little EPO-R protein was detected on immunoblots of
extracts from normal cardiovascular tissues. While in preclinical studies high-dosed
ESAs reduced the myocardial infarct volume and improved contractile properties
following ischemia, human placebo-controlled clinical trials failed to demonstrate clear
beneficial effects of ESAs in patients with coronary syndrome or myocardial infarct.
ESA therapy is currently used to prevent red blood cell transfusions in anemic patients
with chronic kidney disease or chemotherapy for cancer and is being explored as an
anti-anemia treatment in patients with heart disease. However, because blood viscosity
increases and blood pressure may rise with hematocrit, hemoglobin concentrations
should not be raised above indicated levels.
Keywords: Recombinant human erythropoietin (rhEPO), erythropoiesis stimulating
agents (ESAs), darbepoetin alfa, erythropoietin receptor, heart failure, myocardial
infarct, CD34+ stem cells, angiogenesis, endothelial cells, tissue protection.
