title: MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice.
abstract: Transgenic sickle mice expressing β(S) hemoglobin have activated vascular endothelium in multiple organs that exhibits enhanced expression of NF-ĸB and adhesion molecules and promotes microvascular stasis in sickle, but not normal, mice in response to hypoxia/reoxygenation (H/R), or heme. Induction of heme oxygenase-1 (HO-1) or administration of its products, carbon monoxide (CO) or biliverdin, inhibits microvascular stasis in sickle mice. Infusion of human hemoglobin conjugated with polyethylene glycol and saturated with CO (MP4CO) markedly induced hepatic HO-1 activity and inhibited NF-ĸB activation and H/R-induced microvascular stasis in sickle mice. These effects were mediated by CO; saline or MP4 saturated with O2 (MP4OX) had little to no effect on H/R-induced stasis, though unmodified oxyhemoglobin exacerbated stasis. The HO-1 inhibitor, tin protoporphyrin, blocked MP4CO protection, consistent with HO-1 involvement in the protection afforded by MP4CO. MP4CO also induced nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), an important transcriptional regulator of HO-1 and other antioxidant genes. In a heterozygous (hemoglobin-AS) sickle mouse model, intravenous hemin induced cardiovascular collapse and mortality within 120 minutes, which was significantly reduced by MP4CO, but not MP4OX. These data demonstrate that MP4CO induces cytoprotective Nrf2 and HO-1 and decreases NF-ĸB activation, microvascular stasis, and mortality in transgenic sickle mouse models.
authors.affiliation: Hematology, Oncology, and Transplantation, University of Minnesota Medical School, Minneapolis, MN; and.
authors.forename: John D
authors.initials: JD
authors.lastname: Belcher
authors.forename: Mark
authors.initials: M
authors.lastname: Young
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Chen
authors.forename: Julia
authors.initials: J
authors.lastname: Nguyen
authors.forename: Kenneth
authors.initials: K
authors.lastname: Burhop
authors.forename: Phuc
authors.initials: P
authors.lastname: Tran
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Vercellotti
mesh_terms: D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D006139:Guaiacol / Q000031:analogs & derivatives; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006427:Hemin / Q000378:metabolism / Q000494:pharmacology; D006454:Hemoglobins / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D008297:Male; D008301:Maleimides / Q000378:metabolism / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011092:Polyethylene Glycols / Q000378:metabolism / Q000494:pharmacology*; D014657:Vasculitis / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality
chemical_list: D006454:Hemoglobins; C000620499:MP4CO hemoglobin; D008301:Maleimides; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; C493836:maleimide-polyethylene glycol-modified hemoglobin, MP4; D011092:Polyethylene Glycols; C013738:zingerone; D006139:Guaiacol; D006427:Hemin; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
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