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PubMed2006

Differential utilization by Haemophilus influenzae of haemoglobin complexed to the three human haptoglobin phenotypes.

Haemophilus influenzae has an absolute requirement for heme, which may be supplied as the haemoglobin-haptoglobin complex. Utilization of haemoglobin-haptoglobin by H. influenzae is mediated by a family of proteins termed the haemoglobin-haptoglobin binding proteins (Hgps), of which a given strain may contain up to four genes. Human haptoglobin occurs in three phenotypes (1-1, 2-1 and 2-2). Using mutant derivatives of an H. influenzae type b strain that expressed single Hgps we analysed the ability of each Hgp to utilize haemoglobin complexed to the various haptoglobin phenotypes. A strain expressing only HgpB was able to utilize haemoglobin bound to all haptoglobin phenotypes significantly better than strains expressing either HgpA or HgpC.

Bacterial Proteins↗

PubMed2005

Binding of acellular, native and cross-linked human hemoglobins to haptoglobin: enhanced distribution and clearance in the rat.

It is well established that hemoglobin resulting from red cell lysis binds to haptoglobin in plasma to form a complex. The increased molecular size precludes its filtration by the kidneys, redirecting it toward hepatocellular entry. Chemically cross-linked hemoglobins are designed to be resistant to renal excretion, even in the absence of haptoglobin. The manner in which binding to haptoglobin influences the pharmacokinetics of acellular cross-linked and native hemoglobins was investigated after intravenous injection of radiolabeled native human hemoglobin and trimesyl-(Lys82)beta-(Lys82)beta cross-linked human hemoglobin, at trace doses, into rats. Under these conditions, there is sufficient plasma haptoglobin for binding with hemoglobin. In vitro binding assayed by size-exclusion chromatography for bound and free hemoglobin revealed that, at <8 muM hemoglobin, native human hemoglobin was completely bound to rat haptoglobin, whereas only approximately 30% of trimesyl-(Lys82)beta-(Lys82)beta cross-linked hemoglobin was bound. Plasma disappearance of low doses (0.31 mumol/kg) of native and cross-linked hemoglobins was monoexponential (half-life = 23 and 33 min, respectively). The volume of distribution (40 vs. 19 ml/kg) and plasma clearance (1.22 vs. 0.4 ml.min(-1).kg(-1)) were higher for native than for cross-linked hemoglobin. Native and cross-linked human hemoglobins were found primarily in the liver, and not in the kidney, heart, lung, or spleen, mostly as degradation products. These pharmacokinetic findings suggest that the binding of hemoglobin to haptoglobin enhances its hepatocellular entry, clearance, and distribution.

Animals↗

PubMed2004

Haptoglobin expression and activity during coronary collateralization.

Coronary collateral development relies on the coordinated secretion of growth factors. However, alone they are insufficient for permanent collateral growth. We utilized proteomics to identify other important proteins in the extracellular environment that could facilitate collateralization. Chronically instrumented dogs developed coronary collaterals by the repetitive occlusion method. Subendocardial (0.19 +/- 0.04, 0.27 +/- 0.06, 0.48 +/- 0.10, and 0.81 +/- 0.11 ml x min(-1) x g(-1) on days 1, 7, 14, and 21, respectively) and subepicardial (0.14 +/- 0.01, 0.36 +/- 0.06, 0.51 +/- 0.07, and 0.71 +/- 0.08 ml x min(-1) x g(-1) on days 1, 7, 14, and 21, respectively) blood flow increased in animals subjected to repetitive occlusion. Sham animals exhibited no changes in blood flow. Myocardial interstitial fluid (MIF) from both groups was analyzed by two-dimensional electrophoresis with matrix-assisted laser desorption/ionization time-of-flight identification. The acute-phase protein haptoglobin was identified in the group subjected to repetitive occlusion. ELISA of MIF showed haptoglobin to be elevated at all time points of collateral development compared with sham, with maximal production on day 7. Purified haptoglobin dose dependently stimulated endothelial cells to form tubes and vascular smooth muscle cells to migrate. Purified haptoglobin did not stimulate proliferation of either cell type. The relative contribution of haptoglobin to the chemotactic properties of MIF was tested using a neutralizing antibody. Neutralized MIF could not stimulate smooth muscle cells to migrate at any time during collateral development. Endothelial cell tube formation was inhibited after the midpoint of collateralization. Therefore, the acute-phase protein haptoglobin plays a critical role during coronary collateralization.

Animals↗

PubMed2004

Haptoglobin modifies the hemochromatosis phenotype in mice.

Classic hereditary hemochromatosis (HH) is a common genetic disorder of iron metabolism caused by a mutation in the HFE gene. Whereas the prevalence of the mutation is very high, the clinical penetrance of the disease is low, suggesting that the HFE mutation is a necessary but not sufficient cause of clinical HH. Several candidate modifier genes have been proposed in mice and humans, including haptoglobin. Haptoglobin is the plasma protein with the highest binding affinity for hemoglobin. It delivers free plasma hemoglobin to the reticuloendothelial system, thus reducing loss of hemoglobin through the glomeruli and allowing heme-iron recycling. To gain insight into the role of haptoglobin as a modifier gene in HH, we used Hfe and haptoglobin double-null mice. Here, we show that Hfe and haptoglobin compound mutant mice accumulate significantly less hepatic iron than Hfe-null mice, thus demonstrating that haptoglobin-mediated heme-iron recovery may contribute significantly to iron loading in HH.

Animals↗

PubMed1995

Measurements of haptoglobin by the reaction with concanavalin A in sera of patients with ovarian tumours.

The concentration of haptoglobin in sera of healthy women and patients with non-malignant and malignant ovarian tumours was measured by two methods, i.e. complex formation with haemoglobin and complex formation with concanavalin A. High correlation (r = 0.74) between both the methods was found in the group of healthy women, but correlation coefficients were much lower in the group of non-malignant and malignant tumours (r = 0.42 and 0.37, respectively). Direct determinations of haptoglobin, and calculation of the ratio of haptoglobin bound to concanavalin A to haptoglobin bound to haemoglobin revealed statistically significant differences among the examined groups. Comparison of two methods of haptoglobin quantitation suggest that processes connected with ovarian disorders may alter the glycosylation of haptoglobin oligosaccharide chains.

Adult↗

PubMed2002

Iron status in black persons is not influenced by haptoglobin polymorphism.

Iron status in man is influenced by environmental and genetic factors. The molecular variation of haptoglobin is one of the genetic factors influencing iron status in Caucasians. Differences in iron metabolism between blacks and whites have been reported. We wanted to investigate the effect of haptoglobin polymorphism on iron status in blacks. We studied 300 African subjects who were apparently healthy with normal erythrocyte sedimentation rate and with no increase in dietary iron because of traditional beer consumption. We determined haptoglobin (Hp) phenotypes using starch gel electrophoresis and measured indirect iron status indices using standard methods. We compared iron status indices according to haptoglobin type. Ninety two individuals (31%) had Hp 1-1, 114 persons (38%) had Hp 2-1, 20 subjects (7%) had Hp 2-1(Modified) and 54 individuals (18%) had Hp 2-2 type. Haptoglobin was not detectable in 19 subjects and Hp 2-1(Johnson) was found in one subject. In both males and females, serum iron concentration, total iron binding capacity, transferrin saturation and ferritin concentration were not different with regard to Hp phenotype. These results suggest that haptoglobin phenotypic variation may not be a factor which influences iron status in black persons.

Adolescent↗

PubMed2006

Influence of human haptoglobin polymorphism on oxidative stress induced by free hemoglobin on red blood cells.

BACKGROUND: An in vitro study was conducted to determine whether haptoglobin phenotypes differed in their protective effect against oxidative stress induced by extracellular hemoglobin on red blood cells. METHODS: Conjugated dienes and thiobarbituric acid-reactive substances (TBARS) were determined in human red blood cell membranes in the presence of hemoglobin and various concentrations of each type of purified haptoglobin. In addition, the release of K+ and lactate dehydrogenase from red blood cells was measured. RESULTS: A protective effect of haptoglobin was observed in terms of results obtained for the four parameters examined, with significant differences (p<0.001) between the three haptoglobin types; type 1-1 was the most active and type 2-2 the least active. A proportion of oxidative damage was not sensitive to haptoglobin, but to desferrioxamine (an iron chelator), indicating the participation of two actors, hemoglobin and free iron, in the oxidative stress of membrane lipids. CONCLUSIONS: The antioxidant role of haptoglobin and the phenotype dependence were confirmed for preventing possible oxidative damage induced by free hemoglobin and iron release during its catabolism.

Antioxidants↗

PubMed1986

Association between NIDDM, RH blood group, and haptoglobin phenotype. Results from the San Antonio Heart Study.

We examined seven red cell antigen and 10 polymorphic protein phenotypes in 1237 Mexican Americans randomly selected from three San Antonio neighborhoods. Statistically significant associations were found between non-insulin-dependent diabetes mellitus (NIDDM) and RH blood type (X2 = 32.87, df = 10, P = 0.0003) and haptoglobin phenotype (X2 = 9.15, df = 2, P = 0.010). The haptoglobin association showed a dose effect with a single dose of the haptoglobin-1 allele associated with an approximately 50% increase and a double dose of the haptoglobin-1 allele associated with an approximately 100% increase in NIDDM prevalence. Multivariate analysis indicated statistically significant associations between NIDDM and age, sex, adiposity, and neighborhood of residence. However, even after taking these potential confounding variables into account, there was still a significant, independent association between NIDDM and haptoglobin phenotype. The results suggest that the haptoglobin gene may be in linkage disequilibrium with a major susceptibility gene for NIDDM.

Adult↗

PubMed1987

Elimination of bovine haptoglobin from rat circulation.

The rate of elimination from rat circulation of bovine or rat haptoglobin, of their complexes with homologous haemoglobin, and of preparations deprived of the terminal sialic acid (asialo-haptoglobin), was studied. The rate of elimination was identical for bovine haptoglobin and its complexes with bovine or rat haemoglobin (the half-life time, t1/2, was 10 h). The half-life time of complexes of rat haptoglobin with bovine or rat haemoglobin was about 2 h, and it was much shorter than t1/2 for rat haptoglobin (13 h). The shortest half-life time was observed for bovine and rat asialo-haptoglobin, 35 and 15 min, respectively. The elimination curves showed a biphasic or triphasic character, depending on the rate of elimination.

Acute-Phase Proteins↗

PubMed1979

[Haptoglobin levels in premature infants].

A group of 30 preterm babies with no evidence of infections was investigated. They were separated in 3 groups according to the gestational age. In the first group, which included babies 28 to 32 weeks of gestational age, haptoglobin was detected in 5, but in 3, levels were under 25 mg/dl. In the second group, which consisted of babies of 33 to 36 weeks of gestational age, haptoglobin was detected in 6 infants, with levels less than 25 mg/dl in 3. Finally, in the group of babies of 37 to 40 weeks, haptoglobin was presented in 7. Haptoglobin was detected in 18 infants, which means in 60% of patients. Levels of haptoglobin were lower in babies of lower gestational age. Values obtained for haptoglobin levels in this study will be used in diagnostic purposes, for comparation with levels obtained in various pathological conditions.

Female↗

PubMed1988

Complex events in the evolution of the haptoglobin gene cluster in primates.

Southern blot analyses of genomic DNA show that new world monkeys have only one haptoglobin gene but that chimpanzees, gorillas, orangutans, and old world monkeys have three. Humans have two: haptoglobin (Hp) and haptoglobin-related (Hpr). These observations suggest that a triplication of the haptoglobin locus occurred after the divergence of the new world monkeys, followed by a deletion of one locus in humans. To investigate these events, we have cloned the haptoglobin gene cluster in chimpanzee. The organization of the Hp and Hpr genes in chimpanzees is the same as in humans, including a retrovirus-like sequence in the first intron of Hpr. The third gene, which we name Hpp for haptoglobin primate, is 16 kilobases downstream of Hpr. A second copy of the retrovirus-like sequence occurs between Hpr and Hpp. The nucleotide sequence of the chimpanzee Hpp gene suggests that it may code for a functional protein, but the chimpanzee Hpr gene has a single base deletion in exon 5 that causes a frameshift. Comparison of the human and chimpanzee sequences suggests that the human Hpr gene was generated by a homologous unequal crossover between ancestral Hpr and Hpp genes. The crossover point lies within a 1.3-kilobase region containing exon 5 and 500 nucleotides 3' to the genes, but the exact point is obscured by a subsequent gene conversion event.

Animals↗

PubMed1977

[Relationship between haptoglobin types and group G streptococci (author's transl)].

A relationship was found between the haptoglobin types of human sera and the agglutinability of some strains of group G streptococci. Sera with the haptoglobin types Hp 2-2 and Hp 2-1 agglutinate these streptococci to high titers, from 1:200 up to more than 1:6400. On the other hand, the sera with haptoglobin type Hp 1-1 agglutinate not more than up to titers of 1:16 (mostly lower). Out of 102 strains of group G streptococci only 3 showed this characteristic phenomenon. This study was undertaken in order to elucidate whether the Hp 2-2 and Hp 2-1 proteins have antibody activity. Incubation of Hp 2-2 or Hp 2-1 sera with antihaptoglobin antisera or with anti-Hp 2-antiserum did not change the agglutinating activity but the haptoglobin was eliminated from the sera. Absorption of Hp 2-2 and Hp 2-1 sera with these group G streptococci lowered the titers significantly but the haptoglobins are detectable as in the non-absorbed sera. Sera with haptoglobin 1-1 contain an inhibitor. Mixing of Hp 2-2 and Hp 2-1 sera with high agglutinating titers with Hp 1-1 sera (low titers) was followed by a significant decrease of the titer.

Agglutination↗

PubMed1981

High frequency of low plasma haptoglobin values found in hemophilia A patients on prophylactic treatment with factor VIII concentrates - a sign of hemolysis?

Low plasma haptoglobin values have been observed in hemophilia A patients on regular prophylactic treatment with factor VIII concentrates. Two of 3 patients treated with fraction I-0 (Kabi) and 7 of 11 patients treated with high-purity concentrates (Hyland) had low haptoglobin values. Four of 8 patients who were treated with high-purity concentrates prescreened for a low content of anti-A and anti-B immunoglobulins still showed low haptoglobin levels. Unexpectedly, 2 patients of blood group 0 showed low haptoglobin values. The presence of irregular erythrocyte alloantibodies and/or other contaminants of the concentrates might thus also be a cause of hemolysis resulting in an increased consumption of haptoglobin. Elevated lactate dehydrogenase levels were also frequent. No correlations were found between albumin, aspartate or alanine aminotransferase levels and haptoglobin levels.

Adolescent↗

PubMed1983

Biosynthesis and processing of rat haptoglobin.

Native rat haptoglobin is an heterotetramer consisting of two alpha-subunits (Mr = approximately 9,500) and two glycosylated beta-subunits (Mr = approximately 38,000) joined by interchain disulfide bonds. We previously reported (Haugen, T. H., Hanley, J. M., and Heath, E. C. (1981) J. Biol. Chem. 256, 1055-1057) that the synthesis of rat haptoglobin is encoded by a single mRNA, and that the primary in vitro translation product is a single polypeptide, preprohaptoglobin (Mr = approximately 40,000), that contains an NH2-terminal signal sequence as well as an alpha-subunit region and a beta-subunit region. We now report that partial sequence analysis of preprohaptoglobin indicates that the protein possesses an NH2-terminal hydrophobic signal peptide of 18 amino acid residues, followed directly by the alpha-subunit region, with the beta-subunit region located in the carboxyl-terminal portion of the protein. The co-translationally processed translation product consists of a core glycosylated polypeptide, prohaptoglobin (Mr = approximately 45,000), that is devoid of the signal sequence and possesses both the alpha-subunit and beta-subunit regions of haptoglobin. Pulse-chase experiments in cultures of isolated hepatocytes, and analysis of haptoglobin biosynthetic intermediates in the various subcellular organelles of in vivo labeled rat liver indicate that: (a) in the endoplasmic reticulum, core glycosylated prohaptoglobin is dimerized and a portion of the protein is processed to form the individual alpha- and beta-subunits; (b) the carbohydrate side chains of prohaptoglobin and of core glycosylated beta-subunit (Mr = approximately 35,000) are converted to complex, sialylated side chains in the Golgi apparatus, resulting in the formation of fully glycosylated prohaptoglobin (Mr = approximately 48,000) and beta-subunit (Mr = approximately 38,000), and these forms of the protein, as well as the alpha-subunit (Mr = approximately 9,500), are secreted; (c) inhibition of glycosylation with tunicamycin does not significantly affect the rate of synthesis, processing, or secretion of the various haptoglobin polypeptides in isolated hepatocytes; (d) similar experiments conducted in the presence of colchicine also had no effect on the rate of synthesis and processing of the intermediates; and (e) the species of haptoglobin secreted in vivo and from isolated hepatocytes consist of approximately 60-70% in the form of the alpha 2 beta 2 tetramer, and the remainder as dimerized prohaptoglobin. Presumably, secreted prohaptoglobin may be processed to the native subunit structure after secretion, as we demonstrated that incubation of prohaptoglobin with either normal rat serum, rat plasma, or with the sera of other animal species results in its conversion to the corresponding alpha- and beta-subunits of the native protein.

Amino Acids↗

PubMed1980

Haptoglobin typing and quantitation in normal Chinese females and gynecologic cancer patients.

Haptoglobin typing with polyacrylamide gel electrophoresis and guaiacol staining was performed in 1028 sera, including 215 cases of various gynecologic malignancies, 45 of benign gynecologic tumors, 99 of pregnancy, 2 of infection, and 667 of healthy subjects as controls. In the control group, excluding 9 cases of hypohaptoglobinemia, the incidences of haptoglobin type 1-1, 2-1, and 2-2 were 12.00%, 41.03%, and 46.96% respectively. The Hp alpha 1 gene frequency was 0.3251. In cervical cancer and ovarian cancer, the incidence of type 1-1 was lower, while in corpus cancer, it was remarkably elevated. The frequency of Hp alpha 1 gene decreased in cervical cancer but increased in corpus cancer and other miscellaneous gynecologic cancer patients. However, the type distribution of gynecologic malignancy as a group was almost the same as that in the control group. The association of malignancy and haptoglobin types awaits further study. With single radial immunodiffusion technic, haptoglobin quantitation was also performed in 655 cases. In 331 nonpregnant healthy subjects, the mean levels in type 1-1, 2-1, and 2-2 were 118.4, 180.9, and 137.9 mg% respectively. While the haptoglobin level during pregnancy and in most benign gynecologic tumors remained the same as in normal controls, it was significantly elevated in corpus cancer, ovarian cancer and advanced cervical cancers. A close association between malignancy and elevated haptoglobin levels was evident.

Adult↗

PubMed1994

[The role of haptoglobin in asphyxia mechanism (II)--Acute drowning and hanging].

We examined changes in plasma during drowning and hanging to determine the mechanism of acute asphyxia. Rabbits were used for the acute drowning and hanging experiments (using artificial sea water or fresh water for the former and complete or incomplete hanging for the latter). The plasma was examined for changes in haptoglobin and total protein contents. For acute drowning, the haptoglobin level reduced dramatically after one minute of inhalation of artificial sea and fresh water by about 46.0% and about 61.0%, respectively. Total protein content showed the same pattern of reduction. Afterward, haptoglobin remained generally unchanged but the total protein content returned to the original level 3 minutes after inhalation. For the handing, the haptoglobin level reduced within 1 minute. When respiratory arrest was near, both haptoglobin and total protein contents rose gradually. The changes in the haptoglobin level caused by hanging were similar to those that occur in acute asphxia when the air passage is completely obstructed and in subacute asphxia when the air passage is strangulated. Totally different and unique patterns were seen in association with drowning in comparison with obstructive asphyxia. These results suggested that the pathological physiology of acute drowning is different from that of fatal neck compression or other types of acute asphyxia.

Acute Disease↗

PubMed1996

Biological and clinical significance of haptoglobin polymorphism in humans.

Haptoglobin is a hemoglobin-binding protein expressed by a genetic polymorphism as three major phenotypes: 1-1, 2-1, and 2-2. Most attention has been paid to determining haptoglobin phenotype as a genetic fingerprint used in forensic medicine. More recently, several functional differences between haptoglobin phenotypes have been demonstrated that appear to have important biological and clinical consequences. Haptoglobin polymorphism is associated with the prevalence and clinical evolution of many inflammatory diseases, including infections, atherosclerosis, and autoimmune disorders. These effects are explained by a phenotype-dependent modulation of oxidative stress and prostaglandin synthesis. Recent evidence is growing that haptoglobin is involved in the immune response as well. The strong genetic pressure favoring the 2-2 phenotype suggests an important role of haptoglobin in human pathology.

Chemistry, Clinical↗

PubMedDate not supplied

Haptoglobin in rheumatic fever.

Serum haptoglobin levels were studied in rheumatic fever and in established rheumatic heart disease to find whether rheumatic activity influenced serum haptoglobin levels. The study was carried out on 90 subjects of paediatric age group, comprising 30 children suffering from acute rheumatic fever (Group I) and Group II of 30 children of established rheumatic heart disease (not having rheumatic activity). They were matched with group III of 30 normal children of the same age as controls. Levels of ASO titre, C-reactive protein, serum haptoglobin and ESR were estimated in all cases of study and control groups. Estimations of serum haptoglobin levels and ESR were repeated in all children of rheumatic fever after 2 weeks. Haptoglobin levels were estimated by electrophoresis on a cellulose acetate paper. In healthy children (Group III) mean serum haptoglobin was 92.2 +/- 19.77 mg%. This was significantly lower when compared with acute rheumatic fever group before treatment (606.58 +/- 171.04 mg%) and rheumatic heart disease group (120.8 +/- 26.03 mg%).

Child↗