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PubMed2004

Antioxidant role of human haptoglobin.

Human plasma haptoglobin (Hp) is classified according to three phenotypes: Hp 1-1, 2-1, and 2-2 attributed by their two common alleles 1 and 2. Clinically, the 2-2 phenotype is associated with the risk of cardiovascular diseases and diabetes mellitus in patients. In this study, we demonstrate that Hp is an extremely potent antioxidant, which directly protects low density lipoprotein from Cu(2+)-induced oxidation. Its potency was markedly superior to probucol (one of the most potent antioxidants). Ranking of the IC(50) of antioxidant activity was as follows: Hp 1-1 greater, similar Hp 2-1 greater, similar Hp 2-2 greater, similar probucol greater, similar vitamin E. Blockage of disulfide linkages between Hp subunits, not only abolished the alpha-helical content but also diminished the ability of Hp to form a complex with hemoglobin. The modified Hp subunits exerted almost 4 times greater antioxidant activity than that of native Hp. To investigate the antioxidant role of Hp on the cellular level, the cDNA of Hp 1-1 was cloned, introduced into the pcDNA3.0 vector which contains the cytomega lovirus promoter and transfected into chinese hamster ovary (CHO)-K1 cells. Following transfection, CHO cells were able to express Hp 1-1 protein and significantly (p < 0.001) elevated cell tolerance against oxidative stress. Transfected cells showed 2-fold higher resistance to hydrogen peroxide exposure for 24 h compared to control cells. Thus, Hp plays a provocative antioxidant role as demonstrated by our in vitro and ex vivo studies.

Animals↗
PubMed2005

High-throughput MS-based protein phenotyping: application to haptoglobin.

A high-throughput affinity capture and reduction approach was developed for phenotype and post-translational modification analysis of a complexed globular protein, haptoglobin (Hp), directly from human plasma. Hp was selectively retrieved utilizing anti-Hp antibodies immobilized onto affinity pipette tips, eluted onto a formatted mass spectrometer target for reduction of Hp alpha-chains (Hpalpha1 and Hpalpha2) and subjected to subsequent MALDI-MS analysis. The affinity capture and reduction approach was originally developed from a pre-extraction reduction methodology that was optimized to an affinity capture post-reduction technique for intact Hp alpha-chain variant analysis, phenotype classification and ensuing post-translational variant detection. Three common Hp phenotypes (1-1, 2-1 and 2-2) were assigned according to detection of Hpalpha1 and/or Hpalpha2 reduced intact chain(s) average mass(es). The affinity capture post-reduction approach was scaled for high-throughput Hp alpha-chain phenotype analysis from a normal plasma cohort. The entire sample cohort was successfully analyzed and phenotyped using the developed approach. Additionally, Hp post-translational variants were detected and assigned via accurate MS analyses. The results of this study suggest use of the methodology in future analyses of other similarly complexed proteins and in normal versus disease cohort population proteomics studies.

Haptoglobins↗
PubMed2006

Proteomic analysis of plasma from patients with systemic lupus erythematosus: increased presence of haptoglobin alpha2 polypeptide chains over the alpha1 isoforms.

In the present study plasma samples from 15 systemic lupus erythematosus (SLE) patients and 16 healthy controls of initially unknown haptoglobin (Hp) phenotype were separated by 2-DE, and tryptic digests of the excised Hpalpha polypeptide chain spots were analyzed by MALDI-TOF-MS. Selected tryptic peptides were sequenced by nano-(n)ESI-IT MS/MS. The six major Hp phenotypes were present, although with distinct frequencies in controls and SLE patients. Thus, there were an increased proportion of SLE patients with Hp 2-2, or Hp 2-1S phenotypes. The Hp phenotype distribution resulted in allele frequencies of 0 625 (Hp(2)), 0.281 (Hp(1S)), and 0.093 (Hp(1F)) in healthy controls, correlating fairly well with the allele frequencies of European populations. In contrast, the Hp allele frequencies of the SLE patients were 0.733 (Hp(2)), 0.233 (Hp(1S)), and 0.033 (Hp1(1F)), which clearly indicated an increased frequency of Hp(2), a similar proportion of Hp(1S) and a diminished proportion of Hp(1F) in SLE patients compared with that in healthy controls. Preferential Hpalpha2 expression in SLE patients may contribute to some of the clinical manifestations of the disease such as hypergammaglobulinemia, systemic vasculitis, and cardiovascular disorders.

Biomarkers↗
PubMed2006

Proteotyping of human haptoglobin by MALDI-TOF profiling: Phenotype distribution in a population of toxic oil syndrome patients.

Toxic oil syndrome (TOS) is a disease that appeared in Spain in 1981 as a consequence of the ingestion of an aniline-adulterated oil illegally marketed as edible. TOS affected more than 20 000 people and produced over 400 deaths in the first 18 months after the outbreak. There is evidence that genetic factors could play a role in the susceptibility of individuals towards the disease. Recently, we suggested that haptoglobin (Hp) polymorphism could also play a role in TOS. To provide a rapid method for high-throughput Hp phenotyping, we developed a two-step MALDI-TOF procedure that allows specific identification of the three common Hp alpha chains. Resolution of the homologous alpha-1s and alpha-1f chains, which have a mass difference of only 0.043 Da, is obtained after guanidination of the protein with O-methylisourea. We applied this procedure to the study of the distribution of the Hp alleles HP(1s), HP(1f), HP(2) in a control versus a TOS-affected population, both originally exposed to the toxic oil. The MALDI-TOF proteotyping method was validated by a parallel analysis of the serum samples by 2-DE. Data obtained from 54 TOS cases and 48 control individuals indicate significant differences in the distribution of Hp phenotypes in the two populations.

Biomarkers↗
PubMed1993

Effect of interleukin-11 on the levels of mRNAs encoding heme oxygenase and haptoglobin in human HepG2 hepatoma cells.

Effect of recombinant human interleukin-11 (rhIL-11) on the expression of transcripts encoding microsomal heme oxygenase (HO), the rate-limiting enzyme in heme catabolism, and haptoglobin (Hpt), a major acute-phase protein, were examined in human HepG2 hepatoma cells. Treatment of HepG2 cells with rhIL-11 elicited an increase in HO mRNA in a dose- and a time-dependent fashion. The dose response curve, its magnitude of response and its time course were similar to those observed with recombinant human interleukin-6 (rhIL-6). In contrast, rhIL-11 had a far smaller effect on the level of Hpt mRNA than did rhIL-6. These findings demonstrate that the two cytokines are similar in regulating heme catabolism, while markedly different in inducing certain acute-phase proteins.

Gene Expression↗
PubMed1993

The 70 kD rat liver nucleoplasmic protein binding hormone responsive element of rat haptoglobin gene shares size, charge and epitopes with lamin A.

The 70 kD rat liver nucleoplasmic protein was shown previously to display binding affinity for hormone responsive element of rat haptoglobin gene which markedly increased during the acute-phase reaction. In this work the possibility of its structural homology to lamin-type intermediate filament proteins is assessed. The results of two-dimensional Southwestern and Western analyses pinpointed to size, charge and epitope homology between the 70 kD rat liver nucleoplasmic protein binding the hormone responsive element and the lamin A constituent of nuclear matrix structure.

Animals↗
PubMed2001

Induction of haptoglobin by all-trans retinoic acid in THP-1 human monocytic cell line.

Haptoglobin (Hp) is one of the acute-phase proteins and is mainly synthesized in the liver. During our study on the differentiation of leukemia cells, we have found that Hp is synthesized in human monocytic cells by all-trans retinoic acid (ATRA). The synthesis of Hp by ATRA is induced in a dose- and time-dependent manner. Hp cDNA cloned from ATRA-treated THP-1 cells corresponds to the Hp alpha 2(FS)-beta form. Whereas ATRA acted as a strong inducer in THP-1 cells, IL-1 beta, TNF-alpha, IL-6, and LPS had little effect on Hp gene expression in these cells. These findings suggest that THP-1 cells express the Hp gene through a signal pathway different from hepatocytes, and that ATRA is a potent Hp-inducer in these cells.

Cell Differentiation↗
PubMed1995

The DNA binding affinity of rat liver nucleoproteins to the regulatory elements of the haptoglobin and alpha 2-macroglobulin genes.

Transcriptional regulation and binding interactions between soluble nucleoproteins and the hormone response elements (REs) of the rat haptoglobin (Hp) and alpha 2-macroglobulin (alpha 2MG) genes was examined in the livers of rats during the acute-phase reaction. Our results demonstrate that the elevation of the Hp and alpha 2MG genes' transcription rates in acute-phase liver relies essentially on an increase in the binding-affinity of pre-existing soluble nucleoproteins, enhancing their capability to bind the examined cis-regulatory elements. The 35kD nucleoprotein that displayed an acute-phase inducible affinity to bind hormone REs of rat Hp and alpha 2MG genes, was identified as a C/EBP beta isoform.

Acute-Phase Proteins↗
PubMed1998

Participation of two isoforms of C/EBPbeta transcription factor in the acute-phase regulation of the rat haptoglobin gene.

Previous analyses of the mechanism of the transcriptional induction of the rat haptoglobin (Hp) gene during acute-phase (AP)-reaction have revealed the involvement of several trans-acting nucleoproteins (NPs) in controlling this process. In this study, by using antibodies against C/EBPbeta factor in Western immunoblot assay, we found that rat liver trans-acting NPs p35 and p20 are two characteristic C/EBPbeta isoforms whose expression is induced under AP-conditions. DNA-binding assays identified the binding sites for these two C/EBPbeta proteins in the functionally defined elements A and C of the rat Hp gene and also revealed that they have specific binding affinity towards these elements. Under non-induced conditions, p35 was the only C/EBPbeta binding factor; however, upon AP-conditions both, 35 kDa- and 20 kDa-C/EBPbeta binding activities were significantly induced suggesting that these interactions are necessary for the activation of the Hp gene. By in vitro phosphorylation assay and selective proteolysis, we also present evidence that p35 requires phosphorylation for its DNA binding ability. Thus, we conclude that increase in binding of C/EBPbeta isoforms during AP-reaction occurs through their upregulation and structural modification.

Acute-Phase Reaction↗
PubMed2002

p53-like protein binding affinity to the hormone responsive element of the haptoglobin gene in fetal rat livers.

In order to identify nucleoproteins involved in transcriptional regulation of the haptoglobin (Hp) gene, fetal rat livers of dams exposed to inflammation on day 19 of pregnancy were used. Previously observed acute phase-dependent elevation of Hp gene transcriptional activity in prenatal liver was accompanied by increased binding affinities of several fetal soluble nucleoproteins and the hormone response element (RE) of the Hp gene (-170/-56). One of these proteins, a hepatic nucleoprotein of 53 kDa, was identified by Western blotting analysis as a protein within the same molecular mass and epitopes as transcription factor p53. Also, in vitro phosphorylation experiments revealed that the examined fetal nucleoprotein could be liable to the same phosphorylative post-translational modification as p53. The obtained results suggest that the fetal 53 kDa-nucleoprotein could be a homologue of transcription factor p53, participating in the transcriptional modulation of the Hp gene throughout prenatal hepatic development.

Animals↗
PubMed1995

A new family of retroviral long terminal repeat elements in the human genome identified by their homologies to an element 5' to the spider monkey haptoglobin gene.

A new family of retroviral long terminal repeats that we name Spm-LTR has been identified as a result of DNA sequence comparisons between the entire GenBank databank and an element, SPHP, located 5' to the haptoglobin gene of spider monkeys. The 18 human Spm-LTR sequences so identified fall into three subtypes. There is no sequence similarity between Spm-LTR elements and any endogenous retroviral LTR sequences previously reported except for general features that define LTRs. However, a previously described repeated sequence (MER-4) forms a portion of the Spm-LTR sequence.

Animals↗
PubMed1988

Haptoglobin phenotyping by polyacrylamide gel isoelectric focusing and its application to simultaneous typing of serum proteins.

A simple isoelectric focusing method for haptoglobin (HP) typing is described. Serum was pretreated first with C. perfringens neuraminidase (CPN) and then with dithiothreitol (DTT). The treated serum was subjected to polyacrylamide gel isoelectric focusing (PAGIF), and the band patterns were detected by immunoblotting. The method could be successfully applied to HP typing of bloodstains as old as 2 months. A slight modification of it enabled HP, complement component C81, and factor I (IF) to be typed simultaneously. The immunoblotting facilitated preservation of HP patterns. Thus, the PAGIF method for HP typing is suitable for routine use in the forensic laboratory.

Blood Proteins↗
PubMed1985

Subtyping of haptoglobin--presentation of a new method.

A method is described for large scale routine phenotyping of haptoglobin (Hp) which allows complete subtyping without prior purification of the Hp molecule. The procedure includes polyacrylamide gel isoelectric focusing of reduced, neuraminidase treated serum or plasma samples, and nitrocellulose blots developed with the immunoperoxidase technique. Different variables including sample treatment, electrofocusing, blotting procedures, and immunoperoxidase visualization are discussed. Characteristic alpha-chain patterns allow identification of the common allotypes 2FS, 2SS, 2FF, IS, IF, and Johnson. Isoelectric variations in the beta-chain may also be recognized. For comparison, two-dimensional Hp-patterns are presented. The results from concurrent typing of 600 samples by ordinary starch gel electrophoresis and by the described isofocusing technique, are evaluated.

Electrophoresis, Polyacrylamide Gel↗
PubMed1982

Polymorphism of the haptoglobin peptides by isoelectric focusing electrophoresis and isoelectric point determinations.

In this investigation, the authors developed two new procedures: a micromethod for haptoglobin purification and the isoelectric focusing electrophoresis on slab polyacrylamide gel for peptide subtyping. These technics are adapted to the study of large sample series for population genetic surveys. The improvements obtained enabled us to disclose in an easy and highly reproducible way the Hp alpha and alpha 2 peptide chains. Electrophoretic separation of the alpha 2 FS, SS, and FF chains were greatly improved. Their frequencies estimated in a sample already investigated by the conventional PAGE presented higher values than previously described. New Hp alpha and alpha 2 mutants were also detected. For the first time, isoelectric points of the Hp peptides were determined; the values obtained are discussed with regard to their known amino acid structure.

Electrophoresis, Polyacrylamide Gel↗
PubMed1985

A new restriction fragment length polymorphism in the haptoglobin gene region.

Direct gene analysis of the haptoglobin gene region was carried out by Southern blotting using an Hp cDNA as probe. Two types of polymorphism were observed: one due to intragenic duplication, is characterized by a constant fragment length difference of 1700bp observed with several enzymes and by complete correspondence with the protein molecular weight polymorphism; the second type, due to point mutation, was represented by two additional restriction sites for Eco RI and Pst I, with a frequency comparable to that of other genes. These two mutations segregated together in families, suggesting that the recently described Hp related gene is closely linked to the Hp gene. Moreover, they were completely associated with each other. The evolutionary significance of this finding is discussed.

Alleles↗
PubMed1975

Haptoglobin, transferrin and serum albumin variants in the Dayaks of Sarawak.

The Land Dayaks and the Sea Kayaks of Sarawak were surveyed for haptoglobin, transferrin and serum albumin variants. The Hp1 gene frequency was 0.385 in 283 Land Dayaks as well as in 205 Sea Kayaks. The TfDChi gene frequency in 283 Land Dayaks was 0.030 and in 188 Sea Kayaks it was 0.040. Serum albumin Medan was found in one of the 188 Sea Kayaks.

Emigration and Immigration↗
PubMed1986

Serum haptoglobin types and leukemia.

Haptoglobin types were determined on 211 patients with leukemia of the four most common types: acute lymphatic (ALL), chronic lymphatic (CLL), acute myeloid (AML), and chronic myeloid leukemia (CML). Frequency distributions of the three common Hp types in patients differed significantly from the control population. A significant increase in the relative incidence of Hp 1-1 was observed in patients with ALL, AML, and CML, but not with CLL. A similar trend was consistent in the data from previously published studies for the same three types of leukemia but not for CLL. Our results and the analysis of data from previous studies, suggest an association of Hp type with some leukemias, which is expressed in a consistent elevation of Hp 1-1 type among leukemia patients with ALL, AML, and CML.

Alleles↗
PubMed1981

Immunological aspects of the focus problem and the genetic type of haptoglobin.

The frequency distribution of the genetic type of haptoglobin in adults affected with a long-term tonsillitis conforms with the standard rate of incidence. In case of a chronic tonsillitis with the suspicion of focus Hp 2-2 is underrepresented. A genetic disposition to the focus disorder which is caused by a slighter immune response is discussed.

Gene Frequency↗