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Oxidized hemoglobin is an endogenous proinflammatory agonist that targets vascular endothelial cells.

ABSTRACT: 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.

SUBMITTER: Silva G

PROVIDER: S-EPMC2785591 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Oxidized hemoglobin is an endogenous proinflammatory agonist that targets vascular endothelial cells.

Silva Gabriela G Jeney Viktoria V Chora Angelo A Larsen Rasmus R Balla Jozsef J Soares Miguel P MP

The Journal of biological chemistry 20090821 43

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 ago ...[more]

PMID: 19700768

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Project description:Although the 30K family proteins are important anti-apoptotic molecules in silkworm hemolymph, the underlying mechanism remains to be investigated. This is especially the case in human vascular endothelial cells (HUVECs). In this study, a 30K protein, 30Kc6, was successfully expressed and purified using the Bac-to-Bac baculovirus expression system in silkworm cells. Furthermore, the 30Kc6 expressed in Escherichia coli was used to generate a polyclonal antibody. Western blot analysis revealed that the antibody could react specifically with the purified 30Kc6 expressed in silkworm cells. The In vitro cell apoptosis model of HUVEC that was induced by oxidized low density lipoprotein (Ox-LDL) and in vivo atherosclerosis rabbit model were constructed and were employed to analyze the protective effects of the silkworm protein 30Kc6 on these models. The results demonstrated that the silkworm protein 30Kc6 significantly enhanced the cell viability in HUVEC cells treated with Ox-LDL, decreased the degree of DNA fragmentation and markedly reduced the level of 8-isoprostane. This could be indicative of the silkworm protein 30Kc6 antagonizing the Ox-LDL-induced cell apoptosis by inhibiting the intracellular reactive oxygen species (ROS) generation. Furthermore, Ox-LDL activated the cell mitogen activated protein kinases (MAPK), especially JNK and p38. As demonstrated with Western analysis, 30Kc6 inhibited Ox-LDL-induced cell apoptosis in HUVEC cells by preventing the MAPK signaling pathways. In vivo data have demonstrated that oral feeding of the silkworm protein 30Kc6 dramatically improved the conditions of the atherosclerotic rabbits by decreasing serum levels of total triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and total cholesterol (TC). Furthermore, 30Kc6 alleviated the extent of lesions in aorta and liver in the atherosclerotic rabbits. These data are not only helpful in understanding the anti-apoptotic mechanism of the 30K family proteins, but also provide important information on prevention and treatment of human cardiovascular diseases.

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Oxidized hemoglobin is an endogenous proinflammatory agonist that targets vascular endothelial cells.

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Oxidized hemoglobin is an endogenous proinflammatory agonist that targets vascular endothelial cells.

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