Oxidized hemoglobin is an endogenous proinflammatory agonist that targets vascular endothelial cells.
Several pathologic conditions are associated with hemolysis, i.e. release of ferrous (Fe(II)) hemoglobin from red blood cells. Oxidation of cell-free hemoglobin produces (Fe(III)) methemoglobin. More extensive oxidation produces (Fe(III)/Fe(IV) O) ferryl hemoglobin. Both cell-free methemoglobin and ferryl hemoglobin are thought to contribute to the pathogenesis of hemolytic disorders. We show hereby that ferryl hemoglobin, but not hemoglobin or methemoglobin, acts as a potent proinflammatory agonist that induces vascular endothelial cells in vitro to rearrange the actin cytoskeleton, forming intercellular gaps and disrupting the integrity of the endothelial cell monolayer. Furthermore, ferryl hemoglobin induces the expression of proinflammatory genes in endothelial cells in vitro, e.g. E-selectin, Icam-1, and Vcam-1, through the activation of the nuclear factor kappaB family of transcription factors. This proinflammatory effect, which requires actin polymerization, involves the activation of the c-Jun N-terminal kinase and the p38 mitogen-activated protein kinase signal transduction pathways. When administered to naïve mice, ferryl hemoglobin induces the recruitment of polymorphonuclear cells, demonstrating that it acts as a proinflammatory agonist in vivo. In conclusion, oxidized hemoglobin, i.e. ferryl hemoglobin, acts as a proinflammatory agonist that targets vascular endothelial cells.
Silva
Gabriela
G
Instituto Gulbenkian de Ciência, Oeiras 2780-156, Portugal.
Jeney
Viktoria
V
Chora
Angelo
A
Larsen
Rasmus
R
Balla
Jozsef
J
Soares
Miguel P
MP
D000818:Animals; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D006454:Hemoglobins / Q000378:metabolism* / Q000494:pharmacology; D006461:Hemolysis; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism* / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008706:Methemoglobin / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D010108:Oxyhemoglobins / Q000378:metabolism* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D015815:Cell Adhesion Molecules; D006454:Hemoglobins; D018836:Inflammation Mediators; D016328:NF-kappa B; D010108:Oxyhemoglobins; C517773:ferrylhemoglobin; D008706:Methemoglobin; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
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