Recombinant human erythropoietin prevents lipolysaccharide-induced vascular hyporeactivity in the rat

Erythropoietin (EPO) is a hypoxia-inducible hormone that is essential for normal erythropoiesis in the bone marrow. Administration of rh-EPO is currently being used for the therapy of anemia associated with chronic renal failure and cancer. Moreover, EPO reduces the organ injury in experimental hemorrhagic as well as in splanchnic artery occlusion shock and preserves cardiac function after experimental cardiac I/R. EPO receptors are widely distributed in the cardiovascular system, including endothelial, smooth muscle, cardiac, and other cell types and non-hematopoietic effects of EPO are increasingly recognized. Thus, the vasculature may be a biological target of EPO. Therefore, the aim of our study was to investigate whether EPO exerts a protective effect in septic shock by modulating vascular dysfunction and hyporeactivity. Rats received EPO (300 U/Kg, i.v.) or vehicle 30 min prior and 1 and 3 hours after LPS (8x106 U/Kg, i.v.). In vivo and ex vivo (aortic rings) experiments were performed to evaluate the vascular response to contracting and vasodilating agents. The expression of iNOS, ICAM-1, PARP, Bcl-xl and Bcl-2 was evaluated by Western blot analysis in the rat aorta. We demonstrate that EPO significantly prevents the LPS-induced vascular hyporeactivity and endothelial dysfunction. Interestingly, EPO inhibited the increase in iNOS, PARP and ICAM-1 expression in the aorta of endotoxemic rats and attenuated the decline in the expression of both Bcl-xl and Bcl-2 caused by LPS. In conclusion our data support the view that EPO has important non-erythropoietic effects protecting organ and tissue against injury and indicate that EPO may be useful in the therapy of patients with septic shock.