Abstract
Heme oxygenase-1 (HO-1) cleaves the porphyrin ring of heme into carbon monoxide, Fe2+, and biliverdin, which is then converted into bilirubin. Heme-derived Fe2+ induces the expression of the iron-sequestering protein ferritin and activates the ATPase Fe2+-secreting pump, which decrease intracellular free Fe2+ content. Based on the antioxidant effect of bilirubin and that of decreased free cellular Fe2+, we questioned whether HO-1 would modulate the expression of proinflammatory genes associated with endothelial cell (EC) activation. We tested this hypothesis specifically for the genes E-selectin (CD62), ICAM-1 (CD54), and VCAM-1 (CD106). We found that HO-1 overexpression in EC inhibited TNF-alpha-mediated E-selectin and VCAM-1, but not ICAM-1 expression, as tested at the RNA and protein level. Heme-driven HO-1 expression had similar effects to those of overexpressed HO-1. In addition, HO-1 inhibited the activation of NF-kappaB, a transcription factor required for TNF-alpha-mediated up-regulation of these genes in EC. Bilirubin and/or Fe2+ chelation mimicked the effects of HO-1, whereas biliverdin or carbon monoxide did not. In conclusion, HO-1 inhibits the expression of proinflammatory genes associated with EC activation via a mechanism that is associated with the inhibition of NF-kappaB activation. This effect of HO-1 is mediated by bilirubin and/or by a decrease of free intracellular Fe2+ but probably not by biliverdin or carbon monoxide.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenoviridae / genetics
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Animals
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Bilirubin / pharmacology
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Carbon Monoxide / pharmacology
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Cattle
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Cell Adhesion Molecules
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Cells, Cultured
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Down-Regulation / drug effects
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Down-Regulation / immunology
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E-Selectin / biosynthesis
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Endothelium, Vascular / cytology
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Endothelium, Vascular / enzymology*
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Endothelium, Vascular / immunology*
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Endothelium, Vascular / metabolism
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Heme / pharmacology
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Heme Oxygenase (Decyclizing) / biosynthesis
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Heme Oxygenase (Decyclizing) / genetics
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Heme Oxygenase (Decyclizing) / physiology*
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Heme Oxygenase-1
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Humans
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Intercellular Adhesion Molecule-1 / biosynthesis
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Iron Chelating Agents / pharmacology
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MAP Kinase Signaling System / immunology
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Membrane Proteins
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Mitogen-Activated Protein Kinases / metabolism
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Mitogen-Activated Protein Kinases / physiology
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / pharmacology
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Swine
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Transduction, Genetic
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / physiology
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Up-Regulation / immunology
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Vascular Cell Adhesion Molecule-1 / biosynthesis
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p38 Mitogen-Activated Protein Kinases
Substances
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Cell Adhesion Molecules
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E-Selectin
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Iron Chelating Agents
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Membrane Proteins
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NF-kappa B
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Recombinant Proteins
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Tumor Necrosis Factor-alpha
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Vascular Cell Adhesion Molecule-1
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Intercellular Adhesion Molecule-1
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Heme
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Carbon Monoxide
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HMOX1 protein, human
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Heme Oxygenase (Decyclizing)
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Heme Oxygenase-1
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Bilirubin