Recombinant human erythropoietin prevents lipopolysaccharide-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 recombinant human-EPO is currently being used for the therapy of anemia associated with chronic renal failure and cancer. Moreover, EPO reduces organ injury in experimental hemorrhagic as well as in splanchnic artery occlusion shock and preserves cardiac function after experimental cardiac I/R. Erythropoietin receptors are widely distributed in the cardiovascular system, including endothelial, smooth muscle, cardiac, and other cell types, and nonhematopoietic 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 before and 1 and 3 h after LPS (8 x 10 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, intercellular adhesion molecule 1, poly(ADP)ribose polymerase, Bcl-xl, and Bcl-2 was evaluated by Western blot analysis in the rat aorta. We demonstrate that EPO significantly prevents LPS-induced vascular hyporeactivity and endothelial dysfunction. Interestingly, EPO inhibits the increase in iNOS, poly(ADP)ribose polymerase, and intercellular adhesion molecule 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 nonerythropoietic effects protecting organ and tissue against injury and indicate that EPO may be useful in the therapy of patients with septic shock.
Dipartimento di Farmacologia Sperimentale, Università degli studi di Napoli, Federico II, Italy.
Roberta d'Emmanuele
Rd
di Villa Bianca
Rosalinda
R
Sorrentino
Emma
E
Mitidieri
Stefania
S
Marzocco
Giuseppina
G
Autore
Christoph
C
Thiemermann
Aldo
A
Pinto
Raffaella
R
Sorrentino
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004921:Erythropoietin / Q000494:pharmacology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D013997:Time Factors; D014652:Vascular Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D051020:bcl-X Protein / Q000378:metabolism
D008070:Lipopolysaccharides; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D051020:bcl-X Protein; D004921:Erythropoietin; D018799:Intercellular Adhesion Molecule-1; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D011065:Poly(ADP-ribose) Polymerases; D000109:Acetylcholine