Microarray identification of functional modules involving Haptoglobin and/or Hemopexin
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE3656 | GEO | 2006/11/01
SECONDARY ACCESSION(S): PRJNA93783
REPOSITORIES: GEO
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Project description:Haptoglobin and Hemopexin are plasma acute phase proteins that bind with high affinity hemoglobin and heme, respectively. Several studies have demonstrated that they have a key role in the protection against oxidative stress and inflammation. However, little is known about the functional modules in which they are involved. To gain insights into this issue, we integrated bioinformatic and experimental approaches to identify genes coexpressed with Haptoglobin or Hemopexin and modulated in Haptoglobin and/or Hemopexin knock-out mice. These genes have a high probability to be functionally related to Haptoglobin and/or Hemopexin. We performed a gene expression analysis of the livers of Hp- and/or Hx-null mice compared to wild-type controls. The mice used in the following experiments, i.e. wild-type (Hp+/Hx+/), Hp-null (Hp-/-Hx+/), Hx-null (Hp+/Hx-/-), and HpHx-null (Hp-/-Hx-/-), were littermates derived by breeding F1 double heterozygous Hp+/-Hx+/- mice in the mixed genetic background C57/BLJ6 X 129Sv. We have three experimental points: Hx-null mice, Hp-null mice and HpHx-null mice. At least 5 adult mice per genotype were perfused via aorta with PBS, sacrificed and their liver pooled. Thirty microgram of total RNA were subjected to direct labeling reaction by incorporation of cyanin 3 (Cy3) or cyanin 5 (Cy5) fluorescent dyes into the cDNA by priming with oligo(dT). Four replicates were set up for each experimental point. In order to exclude artifacts resulting from different dye usage, we employed the dye-swap approach.
2006-10-31 | E-GEOD-3656 | biostudies-arrayexpress
Project description:Haptoglobin is a major serum protein that sequesters free hemoglobin. Moreover, haptoglobin regulates the inflammatory response in the absence of hemoglobin. Conflicting functional outcomes are reported, whereas involvement of NFκB is suggested consistently. Our data indicate that purified haptoglobin induces NFκB-dependent transcription through toll-like receptor 4. Notably, haptoglobin itself is dispensable for this effect. We show here that haptoglobin binds lipopolysaccharides from different bacterial species with micromolar affinities. This finding explains previous divergent observations. Pro-inflammatory responses elicited by purified haptoglobin are caused by heterogeneous lipopolysaccharides associated with the protein. Given its abundance in human serum, haptoglobin constitutes a buffer for serum-borne lipopolysaccharide. Restricted lipopolysaccharide availability dampens inflammatory responses. Concordantly, NFκB activation in primary macrophages is delayed relative to stimulation with pure lipopolysaccharide. Our findings warrant evaluation of therapeutic benefits of haptoglobin for non-hemolytic conditions as well as re-evaluation of purification strategies and will furthermore allow to disentangle mechanisms of haptoglobin-dependent immunoregulation.
2022-10-24 | GSE215916 | GEO
Project description:Host immunity limits iron availability to pathogenic bacteria, but whether immunity limits pathogenic bacteria from accessing host heme, the major source of iron in the body, remains unclear. Using Citrobacter rodentium, a mouse enteric pathogen and Escherichia coli, a major cause of sepsis in humans as models, we find that interleukin-22, a cytokine best known for its ability to promote epithelial barrier function, also suppresses the systemic growth of bacteria by limiting iron availability to the pathogen. Using an unbiased proteomic approach to understand the mechanistic basis of IL-22 dependent iron retention in the host, we have identified that IL-22 induces the production of the plasma hemoglobin scavenger haptoglobin and heme scavenger hemopexin. Moreover, the anti-microbial effect of IL-22 depends on the induction of hemopexin expression, while haptogloblin is dispensable. Impaired pathogen clearance in infected Il22-/- mice was restored by hemopexin administration and hemopexin-deficient mice had increased pathogen loads after infection. These studies reveal a previously unrecognized host defense mechanism regulated by IL-22 that relies on the induction of hemopexin to limit heme availability to bacteria leading to suppression of bacterial growth during systemic infections.
2017-02-03 | PXD005666 | Pride
Project description:After intracranial hemorrhages, heme is released from cell-free hemoglobin. This red blood cell toxin may drive secondary brain injury at the hematoma-brain interface. This study aimed to generate a spatially resolved map of the transcriptome-wide gene expression changes in the heme-exposed brain and define the potential therapeutic activity of the heme-binding protein hemopexin.
2021-11-25 | GSE182127 | GEO
Project description:Severe presentations of malaria emerge as parasites from Plasmodium spp. proliferate and lyse red blood cells (RBC), producing extracellular hemoglobin (HB). The heme prosthetic groups are released upon HB oxidation generating circulating labile heme. Here we asked whether scavenging of extracellular HB and/or labile heme, by haptoglobin (HP) and/or hemopexin (HPX), respectively, is protective against severe presentations of malaria. We found that circulating labile heme is an independent risk factor for cerebral and non-cerebral severe presentations of P. falciparum malaria. Labile heme was negatively correlated with HP and HPX, which were however, not risk factors for severe P. falciparum malaria. Genetic HP and/or HPX deletion in mice led to accumulation of labile heme in plasma and kidneys in response to Plasmodium (chabaudi chabaudi) infection. This was associated with increased mortality and acute kidney injury (AKI) in ageing but not adult mice, corroborated in P. falciparum malaria by a an inverse correlation between HPX and heme with serological markers of AKI. In conclusion, HP and HPX exert an age-dependent protective effect against malaria that counters the pathogenesis of AKI in mice and presumably in humans.
2024-01-30 | GSE253390 | GEO
Project description:Hemoglobin (Hb) released from red blood cells during hemolysis is a trigger of oxidative vascular damage with endothelial cells being a primary target. The Hb and heme scavenger proteins haptoglobin (Hp) and hemopexin (Hx) have been characterized as a sequential defense system with Hp as the primary protector and Hx as a backup when all Hp is depleted during more severe or prolonged hemolysis. The paradigm of sequential protection by the two scavengers is based on observational patient data proposed by Mueller-Eberhardt. In this study we present a mechanistic rationale for these clinical observations using a novel in vitro model of Hb triggered endothelial damage. We identified oxyHb(Fe2+) transformation to ferric Hb(Fe3+), free heme transfer from ferric Hb(Fe3+) to lipoprotein and subsequent oxidative reactions in the lipophilic phase. The accumulation of toxic lipid peroxidation products liberated during oxidation reactions lead to endothelial damage characterized by a specific gene expression pattern, reduced cellular ATP and monolayer disintegration. Quantitative analysis of key biochemical and functional parameters allowed us to precisely define the mechanisms and concentrations required for Hp and Hx to prevent this toxicity. In the case of Hp we defined an exponential relationship between Hp availability relative to oxyHb(Fe2+) and related protective activity. This exponential relationship demonstrates that large Hp quantities are required to prevent Hb toxicity. In contrast, the linear relationship between Hx concentration and protective activity allows for significant protection by the backup scavenger during conditions of large excess of free oxyHb(Fe2+) that occurs when all Hp is consumed. The diverse protective function of Hp and Hx in this model can be explained by the different target specificities of the two proteins.
2018-02-25 | GSE66283 | GEO
Project description:Extracellular hemoglobin (Hb) has been recognized as a disease trigger in hemolytic conditions such as sickle cell disease, malaria and blood transfusion. In vivo, many of the adverse effects of free Hb can be attenuated by the Hb scavenger acute phase protein haptoglobin (Hp). The primary physiologic disturbances that can be caused be free Hb are found within the cardiovascular system and Hb triggered oxidative toxicity towards the endothelium has been promoted as a potential mechanism. The molecular mechanisms of this toxicity as well as of the protective activities of Hp are not yet clear. Within this study we systematically investigated the structural, biochemical and cell biologic nature of Hb toxicity in an endothelial cell system under peroxidative stress. We identified two principal mechanisms of oxidative Hb toxicity that are mediated by globin degradation products and by modified lipoprotein species, respectively. The two damage pathways trigger diverse and discriminative inflammatory and cytotoxic responses. Hp provides structural stabilization of Hb and shields Hb’s oxidative reactions with lipoproteins providing dramatic protection against both pathways of toxicity. By these mechanisms Hp shifts Hb’s destructive pseudo-peroxidative reaction into a potential anti-oxidative function during peroxidative stress. HPAEC: A two color common reference design was chosen with 4-8 independent biological replicates of each condition. Each experimental sample (Cy5 labeled) was hybridized against a non-treated reference sample (Cy3 labeled). HUVEC: A two color common reference design was chosen with 3-4 independent biological replicates of each condition. Each experimental sample (Cy5 labeled) was hybridized against a non-treated reference sample (Cy3 labeled).
2015-04-30 | E-GEOD-46471 | biostudies-arrayexpress
Project description:This research provides novel insights into the underlying mechanism whereby the cyto- and neuro-protective heme binding protein hemopexin can be inactivated by reactive nitrogen species generated during the heme- and cytokine- driven inflammation that accompanies hemolysis. Nitration of amino acids is generally considered a selective and specific effect reflecting biological events. As we describe in a summary in the next paragraph, three tyrosine resides are preferentially targeted that reside in the heme binding site of apo-hemopexin. Hemopexin deficiency states develop in clinical sepsis and such modifications of hemopexin that we have identified and describe could also provide evidence-based guidance to physicians when heme toxicity is driving pathology to assess the timing and extent of hemopexin replenishment therapies and the patient responses to such treatment.
2016-12-13 | MSV000080394 | MassIVE
Project description:Extracellular hemoglobin (Hb) has been recognized as a disease trigger in hemolytic conditions such as sickle cell disease, malaria and blood transfusion. In vivo, many of the adverse effects of free Hb can be attenuated by the Hb scavenger acute phase protein haptoglobin (Hp). The primary physiologic disturbances that can be caused be free Hb are found within the cardiovascular system and Hb triggered oxidative toxicity towards the endothelium has been promoted as a potential mechanism. The molecular mechanisms of this toxicity as well as of the protective activities of Hp are not yet clear. Within this study we systematically investigated the structural, biochemical and cell biologic nature of Hb toxicity in an endothelial cell system under peroxidative stress. We identified two principal mechanisms of oxidative Hb toxicity that are mediated by globin degradation products and by modified lipoprotein species, respectively. The two damage pathways trigger diverse and discriminative inflammatory and cytotoxic responses. Hp provides structural stabilization of Hb and shields Hb’s oxidative reactions with lipoproteins providing dramatic protection against both pathways of toxicity. By these mechanisms Hp shifts Hb’s destructive pseudo-peroxidative reaction into a potential anti-oxidative function during peroxidative stress.
2015-04-30 | GSE46471 | GEO
Project description:Microarray identification of functional modules involving Haptoglobin and/or Hemopexin
| PRJNA93783 | ENA