title: Antisickling fetal hemoglobin reduces hypoxia-inducible factor-1α expression in normoxic sickle mice: microvascular implications.
abstract: Chronic inflammation is a salient feature of sickle cell disease (SCD) and transgenic-knockout sickle (BERK) mice. Inflammation is implicated in the activation of hypoxia-inducible factor-1α (HIF-1α) under normoxic conditions. We hypothesize that, in SCD, inflammation coupled with nitric oxide (NO) depletion will induce expression of HIF-1α, a transcription factor with wide-ranging effects including activation of genes for vasoactive molecules. To this end, we have examined the expression of HIF-1α in normoxic BERK mice expressing exclusively human α- and β(S)- globins, and evaluated the effect of fetal hemoglobin (HbF) in BERK mice (i.e., <1.0%, 20%, and 40% HbF). HbF exerts antisickling and anti-inflammatory effects. Here, we show that HIF-1α is expressed in BERK mice under normoxic conditions, accompanied by increased expression of its vasoactive biomarkers such as VEGF, heme oxygenase-1 (HO-1), and serum ET-1 levels. In BERK mice expressing HbF, HIF-1α expression decreases concomitantly with increasing HbF, commensurately with increased NO bioavailability, and shows a strong inverse correlation with plasma NO metabolites (NOx) levels. Reduced HIF-1α expression is associated with decreased HO-1, VEGF, and ET-1. Notably, arteriolar dilation, enhanced volumetric blood flow, and low blood pressure in normoxic BERK mice all show a trend toward normalization with the introduction of HbF. Also, arginine treatment reduced HIF-1α, as well as VEGF expression in normoxic BERK mice, supporting a role of NO bioavailability in HIF-1α activation. Thus HIF-1α expression in normoxic sickle mice is likely a consequence of chronic inflammation, and HbF exerts an ameliorating effect by decreasing sickling, increasing NO bioavailability, and reducing inflammation.
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA. dk.kaul@einstein.yu.edu
authors.forename: Dhananjay K
authors.initials: DK
authors.lastname: Kaul
authors.forename: Mary E
authors.initials: ME
authors.lastname: Fabry
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Suzuka
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000755:Anemia, Sickle Cell / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D001794:Blood Pressure; D004195:Disease Models, Animal; D015536:Down-Regulation; D019332:Endothelin-1 / Q000097:blood; D005319:Fetal Hemoglobin / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008833:Microcirculation / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D012039:Regional Blood Flow; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014664:Vasodilation; D055542:alpha-Globins / Q000235:genetics / Q000378:metabolism; D055544:beta-Globins / Q000235:genetics / Q000378:metabolism
chemical_list: D019332:Endothelin-1; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D042461:Vascular Endothelial Growth Factor A; D055542:alpha-Globins; D055544:beta-Globins; C467480:vascular endothelial growth factor A, mouse; D009569:Nitric Oxide; D005319:Fetal Hemoglobin; D001120:Arginine; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse