Cardiovascular effects of erythropoietin an update

Abstract

Erythropoietin (EPO) is a therapeutic product of recombinant DNA technology and it has been in clinical use as stimulator of erythropoiesis over the last two decades. Identification of EPO and its receptor (EPOR) in the cardiovascular system expanded understanding of physiological and pathophysiological role of EPO. In experimental models of cardiovascular and cerebrovascular disorders, EPO exerts protection either by preventing apoptosis of cardiac myocytes, smooth muscle cells, and endothelial cells, or by increasing endothelial production of nitric oxide. In addition, EPO stimulates mobilization of progenitor cells from bone marrow thereby accelerating repair of injured endothelium and neovascularization. A novel signal transduction pathway involving EPOR--β-common heteroreceptor is postulated to enhance EPO-mediated tissue protection. A better understanding of the role of β-common receptor signaling as well as development of novel analogs of EPO with enhanced nonhematopoietic protective effects may expand clinical application of EPO in prevention and treatment of cardiovascular and cerebrovascular disorders.

Figure 1. Signaling pathways mediating EPO-induced protection in the cardiovascular system

Binding of EPO to either the homodimeric EPO-receptor (EPOR) complex or the heterotrimeric EPOR-βCR complex first activates Janus tyrosine kinase 2 (Jak2). Phosphorylation and activation of Jak2 recruits secondary messengers and activates secondary signaling pathways including phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), and nuclear factor-κB. Some of the pathways mediating EPO-mediated protection are similar to those mediating erythropoiesis or neuroprotection. In particular, EPO-mediated inhibition of apoptosis involves activation of protein kinase B/Akt to inhibit caspase-9 or activate nuclear factor kappa B (NFκB) or inhibit Bad, or stimulate signal transducer and activator of transcription (STAT), or MAPK pathway to increase anti-apoptotic messengers in the mitochondria including Bcl-2 and Bcl-xL. The most common pathway for EPO-mediated cardioprotection as well as vascular protection is EPO-induced augmentation of nitric oxide (NO) production by PI3K/Akt phosphorylation and activation of endothelial nitric oxide synthase (eNOS). EPO is also shown to regulate intracellular Ca²⁺ by activating phospholipase C (PLC).

Figure 2. Morphological studies of carotid arteries of eNOS-deficient mice undertaken fourteen days after injury

Carotid arteries were stained with standard Verhoeff van-Giessen. Representative photomicrographs of uninjured carotid arteries (A), carotid arteries after injury (B), and injured carotid arteries of eNOS-deficient mice treated with EPO for 14 days (C). The media is demarcated by internal elastic lamina (open arrow) and external elastic lamina (black arrow). Original magnification x200. Size bar = 50 μm. D: Quantitative histomorphometric analyses of medial CSA in carotid arteries of eNOS-deficient mice without (-) and with (+) EPO treatment. Data are shown as means ± SEM (n=4-6). * P<0.05 vs. control uninjured; † P<0.05 vs. uninjured + EPO (ANOVA with Bonferroni’s).