MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice

John D Belcher, Mark Young, Chunsheng Chen, Julia Nguyen, Kenneth Burhop, Phuc Tran, Gregory M Vercellotti

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Abstract

Transgenic sickle mice expressing βS hemoglobin have activated vascular endothelium in multiple organs that exhibits enhanced expression of NF-κB 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-κB activation and H/R-induced microvascular stasis in sickle mice. These effects weremediated 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 factorerythroid 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-κB activation, microvascular stasis, andmortality in transgenic sicklemouse models.

Original languageEnglish (US)
Pages (from-to)2757-2764
Number of pages8
JournalBlood
Volume122
Issue number15
DOIs
StatePublished - Jan 1 2013

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Heme Oxygenase-1
Carbon Monoxide
Modulators
Transgenic Mice
Hemoglobins
Inflammation
Chemical activation
Biliverdine
Sickle Hemoglobin
Oxyhemoglobins
Hemin
Vascular Endothelium
Heme
Adhesion
Antioxidants
Genes
Molecules
Mortality
Liver
Hypoxia

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MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice. / Belcher, John D; Young, Mark; Chen, Chunsheng; Nguyen, Julia; Burhop, Kenneth; Tran, Phuc; Vercellotti, Gregory M.

In: Blood, Vol. 122, No. 15, 01.01.2013, p. 2757-2764.

Research output: Contribution to journalArticle

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abstract = "Transgenic sickle mice expressing βS hemoglobin have activated vascular endothelium in multiple organs that exhibits enhanced expression of NF-κB 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-κB activation and H/R-induced microvascular stasis in sickle mice. These effects weremediated 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 factorerythroid 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-κB activation, microvascular stasis, andmortality in transgenic sicklemouse models.",
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