PMID- 23908468
OWN - NLM
STAT- MEDLINE
DCOM- 20131204
LR  - 20220408
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 122
IP  - 15
DP  - 2013 Oct 10
TI  - MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of 
      HO-1, inflammation, and vaso-occlusion in transgenic sickle mice.
PG  - 2757-64
LID - 10.1182/blood-2013-02-486282 [doi]
AB  - Transgenic sickle mice expressing beta(S) hemoglobin have activated vascular 
      endothelium in multiple organs that exhibits enhanced expression of NF-kB 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-kB 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-kB activation, microvascular stasis, and mortality in transgenic 
      sickle mouse models.
FAU - Belcher, John D
AU  - Belcher JD
AD  - Hematology, Oncology, and Transplantation, University of Minnesota Medical 
      School, Minneapolis, MN; and.
FAU - Young, Mark
AU  - Young M
FAU - Chen, Chunsheng
AU  - Chen C
FAU - Nguyen, Julia
AU  - Nguyen J
FAU - Burhop, Kenneth
AU  - Burhop K
FAU - Tran, Phuc
AU  - Tran P
FAU - Vercellotti, Gregory M
AU  - Vercellotti GM
LA  - eng
GR  - R01 HL114567/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130801
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Hemoglobins)
RN  - 0 (MP4CO hemoglobin)
RN  - 0 (Maleimides)
RN  - 0 (Membrane Proteins)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NF-kappa B)
RN  - 0 (Nfe2l2 protein, mouse)
RN  - 0 (maleimide-polyethylene glycol-modified hemoglobin, MP4)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - 4MMW850892 (zingerone)
RN  - 6JKA7MAH9C (Guaiacol)
RN  - 743LRP9S7N (Hemin)
RN  - 7U1EE4V452 (Carbon Monoxide)
RN  - EC 1.14.14.18 (Heme Oxygenase-1)
RN  - EC 1.14.14.18 (Hmox1 protein, mouse)
SB  - IM
CIN - Blood. 2013 Oct 10;122(15):2535-6. PMID: 24113796
MH  - Anemia, Sickle Cell/*drug therapy/metabolism/mortality
MH  - Animals
MH  - Carbon Monoxide/metabolism/*pharmacology
MH  - Disease Models, Animal
MH  - Female
MH  - Guaiacol/analogs & derivatives
MH  - Heme Oxygenase-1/*metabolism
MH  - Hemin/metabolism/pharmacology
MH  - Hemoglobins/metabolism/*pharmacology
MH  - Humans
MH  - Inflammation/drug therapy/metabolism/mortality
MH  - Male
MH  - Maleimides/metabolism/*pharmacology
MH  - Membrane Proteins/*metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Microcirculation/drug effects/physiology
MH  - NF-E2-Related Factor 2/metabolism
MH  - NF-kappa B/metabolism
MH  - Polyethylene Glycols/metabolism/*pharmacology
MH  - Vasculitis/*drug therapy/metabolism/mortality
PMC - PMC4067504
EDAT- 2013/08/03 06:00
MHDA- 2013/12/16 06:00
PMCR- 2014/10/10
CRDT- 2013/08/03 06:00
PHST- 2013/08/03 06:00 [entrez]
PHST- 2013/08/03 06:00 [pubmed]
PHST- 2013/12/16 06:00 [medline]
PHST- 2014/10/10 00:00 [pmc-release]
AID - S0006-4971(20)49786-1 [pii]
AID - 2013/486282 [pii]
AID - 10.1182/blood-2013-02-486282 [doi]
PST - ppublish
SO  - Blood. 2013 Oct 10;122(15):2757-64. doi: 10.1182/blood-2013-02-486282. Epub 2013 
      Aug 1.