Acellular haemoglobin attenuates hypoxia-inducible factor-1alpha (HIF-1alpha) and its target genes in haemodiluted rats.
Hb (haemoglobin)-based blood substitutes represent a class of therapeutics designed to correct oxygen deficit under conditions of anaemia and traumatic blood loss. The influences of these agents on HIF-1alpha (hypoxia-inducible factor-1alpha) target genes involved in adaptation to hypoxia have so far not been studied. In the study presented here, rats underwent 80% ET (exchange transfusion) with either HS (hetastarch) or a polymerized Hb OG (Oxyglobin). HS induced dramatic EPO (erythropoietin) gene transcription, reaching a maximum at 4 h post-ET. In contrast, OG suppressed EPO transcription until approx. 24 h post-ET. Large plasma EPO levels that were observed post-ET with HS were significantly blunted in animals transfused with OG. OG, unlike HS, induced a sharp increase in HO-1 (haem oxygenase-1) transcription at 4 h, which declined rapidly within 24 h, whereas modest increases in iNOS [inducible (nitric oxide synthase)] and constitutive NOS [eNOS (endothelial NOS)] were detected over the control. Our results demonstrate for the first time that severe haemodilution-induced erythropoietic responses in kidneys were attenuated by a low-oxygen-affinity cell-free Hb and suggest that tissue-specific oxygen-sensing pathways can be influenced by allosterically modified Hbs.
Manalo
Dominador J
DJ
LBVB (Laboratory of Biochemistry and Vascular Biology), Division of Hematology, CBER (Center for Biologics Evaluation and Research), FDA (Food and Drug Administration), NIH (National Institutes of Health), Bethesda, MD 20892, USA.
Buehler
Paul W
PW
Baek
Jin Hyen
JH
Butt
Omer
O
D'agnillo
Felice
F
Alayash
Abdu I
AI
D000818:Animals; D001802:Blood Substitutes / Q000494:pharmacology*; D015687:Cell Hypoxia; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D006438:Hemodilution; D006454:Hemoglobins / Q000494:pharmacology*; D006895:Hydroxyethyl Starch Derivatives / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D014158:Transcription, Genetic
D001802:Blood Substitutes; D006454:Hemoglobins; D006895:Hydroxyethyl Starch Derivatives; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C402601:hemoglobin glutamer-200; D004921:Erythropoietin; D019001:Nitric Oxide Synthase; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D010100:Oxygen