Recombinant human erythropoietin suppresses endothelial cell apoptosis and reduces the ratio of Bax to Bcl-2 proteins in the aortas of apolipoprotein E-deficient mice.
Recent clinical trials have raised concern that therapy with recombinant human erythropoietin (EPO) may increase cardiovascular disease risk, event rate, and mortality. Endothelial cell apoptosis has been implicated in both atherogenesis and in the destabilization and rupture of atheromatous plaques. In the current study, we observed that EPO and the EPO-mimetic peptide EMP-1 markedly suppressed lipopolysaccharide-induced apoptosis in endothelial cell monolayers. Therapeutic concentrations of EPO upregulated Bcl-2 expression and concurrently diminished expression of Bax, resulting in a net decrease in the ratio of Bax to Bcl-2 protein concentrations. In vivo studies demonstrated that EPO receptor is abundantly expressed in murine aorta and that EPO treatment for 10 weeks markedly decreased the ratio of Bax to Bcl-2 protein in the aortas of apolipoprotein E-deficient mice fed a high-fat diet. To our knowledge, these data are the first to reveal a modulation of regulators of the apoptotic pathway in murine aorta by chronic EPO treatment. These observations imply that long-term administration of EPO may have the potential to affect plaque stability.
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200, USA.
Jeffrey S
JS
Warren
Ying
Y
Zhao
Raymond
R
Yung
Anjali
A
Desai
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects*; D004041:Dietary Fats / Q000008:administration & dosage; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004921:Erythropoietin / Q000494:pharmacology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009842:Oligopeptides / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism; D011994:Recombinant Proteins; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D001057:Apolipoproteins E; D004041:Dietary Fats; D008070:Lipopolysaccharides; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein; C543187:valyl-seryl-tryptophyl-phenylalanyl-phenylalanyl-glutamic acid; D004921:Erythropoietin
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