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PubMed2005

Haptoglobin beta chain isoforms in the plasma and peritoneal fluid of women with endometriosis.

OBJECTIVE: To estimate the expression of haptoglobin (Hp) beta chain isoforms in the peritoneal fluid (PF) and plasma (PL) of women with and without endometriosis. DESIGN: Cross-sectional study. SETTING: University hospital. PATIENT(S): Seventy-two patients with endometriosis and 35 controls. INTERVENTION(S): Peritoneal fluid and PL samples were subjected to two-dimensional gel electrophoresis, silver stained, digitally captured, and compared by semiquantitative computerized analysis. MAIN OUTCOME MEASURE(S): Expression of Hp beta chain isoforms. RESULT(S): No significant difference was observed in the frequency of expression of the Hp beta chain isoforms between the two groups. One beta chain isoform (HpbetaE; molecular weight, 38.40 +/- 0.94 kD; and isoelectric point, 5.63 +/- 0.17) had significantly higher expression in both the PF and PL of women with endometriosis than in the PF and PL of controls. No significant difference was observed in HpbetaE expression between women with mild (revised American Fertility Society [rAFS], stage I-II) and severe (rAFS, stage III-IV) endometriosis. In the control group, HpbetaE expression was correlated with the phase of the menstrual cycle. CONCLUSION(S): Women with endometriosis have higher PF and PL levels of HpbetaE. Further investigation should be aimed at producing antibodies against the HpbetaE-specific epitopes to determine whether its measurement may improve the clinical diagnosis of endometriosis.

Adult↗
PubMed2006

Haptoglobin genotype determines myocardial infarct size in diabetic mice.

OBJECTIVES: We sought to understand the importance of oxidative stress in explaining why the haptoglobin (Hp) genotype determines myocardial infarction (MI) size in diabetes mellitus (DM). BACKGROUND: Two common alleles (1 and 2) exist at the Hp locus in humans. The Hp 2 allele is associated with increased MI size in individuals with DM. In vitro, the Hp 2 protein is associated with increased generation of oxidatively active iron, whereas the Hp 1 protein is associated with increased production of the antioxidant cytokine interleukin (IL)-10. METHODS: Myocardial infarction was produced by myocardial ischemia-reperfusion (IR) in DM C57BL/6 mice carrying the Hp 1 or Hp 2 allele. Myocardial oxidative stress after IR was assessed using electrospray ionization mass spectrometry. Redox active iron and IL-10 were measured in the serum after IR. RESULTS: Myocardial infarction size was significantly larger in Hp 2 mice as compared with Hp 1 mice (44.3 +/- 9.3% vs. 21.0 +/- 4.0%, p = 0.03), and these larger infarctions were associated with a significant increase in a panel of hydroxyl-eicosatetraenoic acids. Redox active iron was greater in Hp 2 mice (0.45 +/- 0.11 micromol/l vs. 0.14 +/- 0.05 micromol/l, p = 0.02), whereas IL-10 was greater in Hp 1 mice (85.8 +/- 12.9 pg/microl vs. 46.7 +/- 10.8 pg/microl, p = 0.04) after IR. Administration of an antioxidant (BXT-51072) to Hp 2 mice reduced myocardial injury after IR by more than 80% (p = 0.003), but no myocardial protection was provided by the antioxidant to Hp 1 mice. CONCLUSIONS: The increased MI size in DM Hp 2 mice occurring after IR may be due to increased oxidative stress.

Animals↗
PubMed2006

An improved method for haptoglobin 1-1, 2-1, and 2-2 purification using monoclonal antibody affinity chromatography in the presence of sodium dodecyl sulfate.

Human haptoglobin (Hp) is classified as three phenotypes: Hp 1-1, 2-1, and 2-2. Previously, we had isolated this protein by affinity columns using either hemoglobin or monoclonal antibody (mAb) prepared against Hp beta-chain (clone 8B1-3A). The isolated Hp from both methods, however, contaminates plasma apolipoprotein A-I (apoA-I). In the present report, we have developed a novel affinity column procedure using an mAb prepared against alpha-chain of Hp (clone 3H8) for Hp purification. Plasma was first chromatographed onto the column followed by a normal wash with a buffer containing 0.12 M NaCl and 0.02 M phosphate, pH 7.4 (PBS). The bound proteins were then prewashed with a 0.04% sodium dodecyl sulfate (SDS)-PBS, pH 7.4, to remove the low-affinity bound apoA-I from Hp. Finally, the bound Hp was eluted with a 0.1% SDS-PBS, pH 11, and collected in tubes containing 1 M Tris-HCl, pH 6.8. As a result, the isolated Hp was devoid of apoA-I and was able to retain the biological function by forming an Hp-hemoglobin complex. The homogeneity of each isolated Hp 1-1, 2-1, or 2-2 was greater than 95% with an yield greater than 50%. The procedure described here is significantly improved in time consumption, recovery, and purity. The rationale, design, and optimization for each step are described in detail.

Animals↗
PubMed2006

Caloric restriction inhibits up-regulation of inflammatory cytokines and TNF-alpha, and activates IL-10 and haptoglobin in the plasma of streptozotocin-induced diabetic rats.

Diabetes mellitus is a significant risk factor for cardiovascular diseases, and low-grade systemic inflammation, mediated by oxidative stress, may play a central role. Caloric restriction (CR) has been reported to be effective in reducing oxidative stress during diabetes and moderating the expression of some markers of inflammation that are up-regulated during aging. Forty male Wistar rats were randomly divided into four groups: nondiabetic feeding ad libitum and under CR, and diabetic feeding ad libitum and under CR. The animals were subjected to 30% CR and ad libitum feeding for 9 weeks before the induction of diabetes by intraperitoneal injection with 35 mg/kg body weight streptozotocin. The inflammatory cytokines [interleukin (IL)-1beta, IL-4 and IL-6] and tumor necrosis factor alpha up-regulated in diabetes were found to be significantly depressed by CR, whereas the antiinflammatory mediators, haptoglobin and IL-10 levels, were increased. These results indicated that CR could prevent diabetic complications through suppression of inflammatory responses.

Animals↗
PubMed2004

Purification of human haptoglobin 1-1, 2-1, and 2-2 using monoclonal antibody affinity chromatography.

Similar to blood type, human plasma haptoglobin (Hp) is classified as 3 phenotypes: Hp 1-1, 2-1, or 2-2. The structural and functional relationship between the phenotypes, however, has not been studied in detail due to the complicated and difficult isolation procedures. This report provides a simple protocol that can be used to purify each Hp phenotype. Plasma was first passed through an affinity column coupled with a high affinity Hp monoclonal antibody. The bound material was washed with a buffer containing 0.2M NaCl and 0.02 M phosphate, pH 7.4, eluted at pH 11, and collected in tubes containing 1M Tris-HCl, pH 6.8. The crude Hp fraction was then chromatographed on a HPLC Superose 12 column in 0.05 M ammonium bicarbonate at a flow rate of 0.5 ml/min. The homogeneity of purified Hp 1-1, 2-1, or 2-2 was greater than 95% as judged by SDS-polyacrylamide gel electrophoresis. Essentially, each Hp isolated was not contaminated with hemoglobin and apolipoprotein A-I as that reported from the other methods, and was able to bind hemoglobin. Neuraminidase treatment demonstrated that the purified Hp possessed a carbohydrate moiety, while Western blot analysis confirmed alpha and beta chains corresponding to each Hp 1-1, 2-1, and 2-2 phenotype. The procedures described here represent a significant improvement in current purification methods for the isolation of Hp phenotypes. Circular dichroic spectra showed that the alpha-helical content of Hp 1-1 (29%) was higher than that of Hp 2-1 (22%), and 2-2 (21%). The structural difference with respect to its clinical relevance is discussed.

Animals↗
PubMed2006

Cloning and expression of human haptoglobin subunits in Escherichia coli: delineation of a major antioxidant domain.

Human plasma haptoglobin (Hp) comprises alpha and beta subunits. The alpha subunit is heterogeneous in size, therefore isolation of Hp and its subunits is particularly difficult. Using Escherichia coli, we show that alpha1, alpha2, beta, and alpha2beta chain was abundantly expressed and primarily present in the inclusion bodies consisting of about 30% of the cell-lysate proteins. Each cloned subunit retained its immunoreactivity as confirmed using antibodies specific to alpha or beta chain. By circular dichroism, the structure of each expressed subunit was disordered as compared to the native Hp. The antioxidant activity was found to be associated with both alpha and beta chains when assessed by Cu(2+)-induced oxidation of low density lipoprotein (LDL). Of remarkable interest, the antioxidant activity of beta chain was extremely potent and markedly greater than that of native Hp (3.5x), alpha chain (10x) and probucol (15x). The latter is a clinically proved potent compound used for antioxidant therapy. The "unrestricted" structure of beta subunit may therefore render its availability for free-radical scavenge, which provides a utility for the future design of a "mini-Hp" in antioxidant therapy. It may also provide a new insight in understanding the mechanism involved in the antioxidant nature of Hp.

Antioxidants↗
PubMed2006

Application of pharmacogenomics in the prevention of diabetic cardiovascular disease: mechanistic basis and clinical evidence for utilization of the haptoglobin genotype in determining benefit from antioxidant therapy.

Atherosclerotic cardiovascular disease (CVD) and diabetic vascular disease have been associated with an increase in oxidative stress. Mechanistic studies in vitro and in animals have demonstrated a direct role for oxidatively modified protein and lipid molecules in the pathophysiology of these diseases. As a result of this oxidation hypothesis numerous studies have been carried out over the past 5-10 years testing the ability of antioxidant vitamins to decrease the incidence of these diseases. The general consensus from these studies, involving over 200,000 individuals, has been that antioxidant vitamins do not provide any vascular protection. Moreover, several of these studies have demonstrated that antioxidant supplementation may be associated with an increased incidence of disease and mortality. One reason why these antioxidant vitamins may have failed to demonstrate benefit may have been due to inappropriate patient selection. In this review we provide supporting clinical evidence and a mechanistic basis for utilizing a genetic marker, the haptoglobin (Hp) genotype, in determining whether antioxidant vitamin therapy may or may not be beneficial for a given patient with diabetes.

Animals↗
PubMed2006

Changes in CRP, SAA and haptoglobin produced in response to ovariohysterectomy in healthy bitches and those with pyometra.

The aim of the study was to assess changes in serum C-reactive protein (CRP), serum amyloid A component (SAA) and haptoglobin (Hp) concentrations in healthy bitches and in those with pyometra undergoing ovariohysterectomy, and to establish the usefulness of such determinations for monitoring the postoperative period. Our results indicate that CRP and SAA determinations serve to evaluate the severity of the inflammatory process in pyometra since the concentrations of these acute phase proteins were increased immediately after surgery and diminished thereafter. The CRP and SAA response was rapidly produced while Hp concentrations increased in a more gradual manner. Thus, postoperative concentrations of CRP and SAA provide valuable information on the subsidence of the inflammatory response during the uneventful postoperative period. Our findings also suggest that acute phase proteins might be useful diagnostic markers of early postoperative complications.

Animals↗
PubMed2006

Evaluating the efficacy of serum haptoglobin concentration as an indicator of respiratory-tract disease in dairy calves.

The serum concentration of haptoglobin (S-Hp) was measured in 833 group-housed dairy calves from nine herds in south-west Sweden once at 24-56 days of age to evaluate the potential of S-Hp as an indicator of clinical respiratory-tract disease (CRD). Presence of disease (treated and non-treated) was assessed clinically by farmers and by a project veterinarian visiting the farms every third week. The median S-Hp of healthy calves was 0.06g/L (80% central range: 0.04-0.23), of calves with diarrhoea within the 10 days before sampling 0.07g/L (80% central range: 0.04-0.63), and of calves with CRD within the 14 days before sampling 0.09g/L (80% central range: 0.04-0.69). Eight different cut-off values were used to define a positive S-Hp analysis result: >0.05, >0.06, >0.07, >0.08, >0.09, >0.10, >0.15 and >0.20g/L. A rectal temperature >39.5 degrees C was denoted as fever. A positive result of five different diagnostic tests for CRD was defined as: (1) a positive S-Hp with fever absent, (2) a positive S-Hp with fever present, (3) either a positive S-Hp or fever, (4) both a positive S-Hp and fever, and (5) fever (regardless of S-Hp). The sensitivity (Se) and specificity (Sp) of each test were calculated from regression coefficients of generalized linear mixed models of the binary test results, applying a logit link. Apart from CRD status (within the 14 days before sampling; no or yes), the models included sex (bull or heifer), and for the test based on S-Hp alone, also rectal temperature (fever, no or yes). Confidence intervals (CI) of Se and Sp were estimated by simulation. Based on Se, Sp, and areas under Receiver Operating Characteristics curves, test 3 was considered the best. At optimal performance, giving equal importance to type I and II errors, i.e. at a S-Hp cut-off of 0.15g/L in heifer calves, Se was 0.64 (95% CI 0.50-0.77) and Sp 0.71 (95% CI 0.60-0.80), and at a S-Hp cut-off of 0.08g/L in bulls, Se was 0.52 (95% CI 0.40-0.64) and Sp 0.80 (95% CI 0.74-0.85). The other tests were judged as unsatisfactory indicators of CRD. In heifers, the proportion of CRD-positive calves in the herd was strongly associated with the proportion of test positives (S-Hp or fever; S-HP and fever), suggesting potential as a herd-level indicator.

Animals↗
PubMed1987

Haptoglobin helps diagnose the HELLP syndrome.

In a case of the HELLP syndrome, anemia was absent, and bilirubin and lactic dehydrogenase levels were normal. In combination with minimal microangiopathic changes in red cell morphology, a decrease in serum haptoglobin was useful to corroborate the presence of intravascular hemolysis.

Adult↗
PubMed2003

Quantitative variations of the isoforms in haptoglobin 1-2 and 2-2 individual phenotypes.

Haptoglobin is a hemoglobin-binding protein presenting in humans three distinct phenotypes (Hpt 1-1, Hpt 1-2, or Hpt 2-2). The Hpt 1-2 and Hpt 2-2 phenotypes are in turn represented by populations of isoforms. The relative amounts of the major isoforms of Hpt 1-2 and Hpt 2-2 were found to differ not only in different individuals, but also in the same individual before and after a physical effort. Exercise-dependent changes in the plasma concentrations of ascorbate, urate, alpha-tocopherol, retinol, and glutathione were also observed, but correlations between such changes and those of the amount for any isoform were not found. Samples of Hpt 1-2 or Hpt 2-2 were challenged with oxidants (H(2)O(2) with ferrous ions, spermine-NO, KO(2), and 3-morpholinosydnonimine), but the isoform levels were not altered. Hpt 2-2 isoforms were present in Hpt 1-2, as minor species. Furthermore, different isoforms exhibited different hemoglobin binding abilities. Thus, these parameters should also be taken into consideration in studies correlating Hpt phenotypes prevalence with pathologies or functional differences.

Adult↗
PubMed2002

Involvement of CCAAT/enhancer-binding protein alpha in haptoglobin gene expression by all-trans-retinoic acid.

Several acute-phase plasma proteins, including haptoglobin (Hp), are induced in the liver in response to inflammation. Recently, we found that Hp gene expression is up-regulated by all-trans-retinoic acid (ATRA) in the extrahepatic monocytic cell line, THP-1. To investigate the molecular mechanism underlying ATRA-induced Hp gene expression, we analyzed the induction of transcription factor CCAAT/enhancer-binding protein (C/EBP) isoforms in ATRA-stimulated THP-1 cells and their binding to the Hp promoter. Western blot analysis showed that treatment with ATRA increased C/EBPalpha and beta expression, but decreased that of C/EBPdelta. Electrophoretic mobility shift and supershift assays demonstrated that only C/EBPalpha of the C/EBP isoforms bound to the C/EBP DNA-binding sites in the Hp promoter. Furthermore, when ATRA-dependent Hp induction was inhibited by sodium butyrate or auranofin, induction of C/EBPalpha, but not C/EBPbeta, was also diminished. These results suggest that C/EBPalpha is involved in the activation of Hp gene expression by ATRA in human monocytic cells.

Anti-Inflammatory Agents↗
PubMed2003

Haptoglobin 2-2 phenotype is associated with decreased ferroxidase activity in smokers.

BACKGROUND: Cigarette smoking and the inheritance of Hp 2-2 phenotype have been separately linked to cardiovascular disease. In this study, the combined effects of smoking and the presence of Hp 2-2 type on predisposition to cardiovascular disease were investigated. METHODS: Fasting blood specimens were collected from 489 Jordanian males (228 smokers and 261 nonsmokers). Haptoglobin phenotype was determined by electrophoresis, and lipid profile and ferroxidase activity were determined by spectrophotometric methods. RESULTS: The results show that, irrespective of Hp type, total- and LDL-cholesterol levels were significantly higher in smokers compared with nonsmokers, while levels of HDL-cholesterol and ferroxidase activity were lower in smokers. There was no significant difference between the three Hp types in nonsmokers regarding the lipid profile and ferroxidase activity. In the smokers group, however, serum ferroxidase activity was significantly lower in individuals with Hp 2-2 type compared with that in Hp 1-1 and Hp 2-1 smoker individuals. Smokers with the Hp 2-2 type have significantly higher levels of total- and LDL-cholesterol and lower HDL-cholesterol levels compared with that in nonsmokers expressing the same Hp type. CONCLUSION: These findings demonstrate that smokers with Hp 2-2 phenotype have a decreased antioxidant capacity suggesting that smoking coupled with the inheritance of an Hp-2-2 type predispose to more oxidative stress and cardiovascular disease.

Adolescent↗
PubMed1987

Changes in serum enzymes, lactate, and haptoglobin following acute physical stress in international-class athletes.

Skeletal muscle is rich in creatine kinase (CK), lactate dehydrogenase (LD), and other enzymes. Many reports describe changes in serum CK and LD following exercise. In our study, 11 male international-class medium-distance runners were followed over a 10-month period prior to the 1984 US Olympic Trials. Cardiorespiratory fitness, evaluated through repetitive treadmill testing, was unchanged in our athletes. Total CK increased significantly during the course of training, and the CK-MB activity was higher than that of sedentary individuals; CK-MB never rose to more than 3% of the total CK. Total LD also rose following acute exercise; however, the proportions of the five isoenzymes were unaltered. There was no change in the LD-1/LD-2 ratio from normal. The origin of the increased serum enzymes was believed to be primarily skeletal muscle. A decrease of serum haptoglobin following acute stress was attributed to intravascular hemolysis and binding of hemoglobin. As expected, serum lactate was dramatically increased immediately postexercise.

Adult↗
PubMed1999

Haptoglobin genotype and natural fertility in humans.

OBJECTIVE: To study the possible relation between human natural fertility and haptoglobin (Hp) genotype. DESIGN: Prospective study. SETTING: Maternity departments of local hospitals in two Italian localities. PATIENT(S): Healthy women who had just given birth in the maternity departments of two local hospitals (n = 679). INTERVENTION(S): Venous blood collection for determination of Hp genotype with the use of starch gel electrophoresis of hemoglobin-supplemented serum. MAIN OUTCOME MEASURE(S): Distribution of Hp genotypes in relation to age of puerperae. RESULT(S): In both populations, the proportion of young mothers was much higher among women who were homozygous for the Hp*1 allele (the Hp*1/*1 genotype) than among women who had other Hp genotypes. In addition, the proportion of multiparous women among the older mothers was higher among those with the Hp*1/*1 genotype than among those with other Hp genotypes. CONCLUSION(S): The data suggest that women with the Hp*1/*1 genotype reproduce at an earlier age and have higher natural fertility potential than women with other Hp genotypes.

Adult↗
PubMed2001

Haptoglobin polymorphism as a risk factor for coronary heart disease mortality.

OBJECTIVES: the aim of our study was to evaluate the independent role of the haptoglobin (Hp) polymorphism as a risk factor for coronary heart disease (CHD) mortality. METHODS: within the framework of the longitudinal part of the Belgian Interuniversity Research on Nutrition and Health (BIRNH) survey, a nested case-control study design was performed through matching the 107 deaths from CHD, occurring within a 10-year follow-up period, with three controls for age and gender. RESULTS: the distribution of the Hp types was found to be in Hardy-Weinberg equilibrium. Conditional logistic regression analysis for matched sets revealed that the Hp polymorphism was significantly associated with CHD death. Rather surprisingly, the finding was that Hp 1-1 individuals were at doubled risk for CHD mortality compared with the others, the odds ratio being 2.09 (95% CI: 1.22-3.60). The association was independent from other classical cardiovascular risk factors and the Hp concentration, and of comparable magnitude between men and women. Moreover, evaluating the interaction term in a multiplicative model showed that the Hp type did not play a synergistic role in the prognostic value of established cardiovascular risk factors. CONCLUSION: in contrast to the findings from cross-sectionally based studies, the results from this longitudinal study show that Hp 1-1 individuals are at elevated risk for CHD mortality.

Aged↗
PubMed2003

Haptoglobin elutes from human atherosclerotic coronary arteries--a potential marker of arterial pathology.

BACKGROUND: Molecules which egress from atherosclerotic arteries may function as plasma markers of arterial pathology, but such egress has not been proven with living human coronary arteries. We hypothesised that proteins eluting from the arterial wall may discriminate between atherosclerotic and non-atherosclerotic coronary arteries. METHODS AND RESULTS: During cardiac bypass surgery, 155 sequential fractions of antegradely flushed coronary cardioplegia solution were collected by balloon-cuffed catheter from the coronary sinus in subjects with angiographically extensive (n=30) or minor (n=7) coronary disease. Although plasma was the major source of protein in heavily blood-contaminated samples, under conditions of low blood contamination (<0.5 mg/ml red cell Haemoglobin) coronary circulation-derived protein was detected. N-terminal sequencing of a major 40 kDa band detected by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated 100% homology with beta chain of Haptoglobin (Hpt). Comparison of perfusates from patients with and without significant coronary disease found that the concentration of Hpt was markedly increased in perfusates from atherosclerotic coronary arteries (0.099+/-0.017 microg Hpt/microg Hb) relative to controls (0.016+/-0.008 microg Hpt/microg Hb, P=0.0027). Analysis of peripheral plasma samples of the same subjects, and of a separate cohort of patients, confirmed greater Hpt in those with angiographic coronary disease than in those without disease. CONCLUSIONS: Proteins such as Hpt elute from the human coronary vascular bed and may differentiate between arteries with minor or extensive atherosclerosis. Although the suitability of Hpt as a circulating plasma marker for atherosclerosis remains to be established, the approach used in the present study may permit identification of diverse plasma-detectable markers of atherosclerosis, and the subsequent non-invasive evaluation of in vivo arterial pathology.

Aged↗
PubMed1997

Haptoglobin polymorphism, a genetic risk factor in coronary artery bypass surgery.

Haptoglobin (Hp) 2-2 type has been associated with accumulation of atherosclerotic lesions in essential hypertension. The aim of this study was to investigate the relationship between Hp type and the extension of coronary lesions in 765 male patients who underwent coronary artery bypass grafting (CABG). In this group, relative Hp1 (0.418) and Hp2 (0.582) allele frequencies were comparable with those of the reference population. Candidate CABG patients with a Hp 2-2 type were overrepresented in the younger (< 45 years) age group (P < 0.05). Hp 2-2 patients needed more bypass grafts than Hp 1-1 patients (relative risk 1.92 95% C.I. 1.24-2.96). The Hp 2-2 type was overrepresented among victims of a previous acute myocardial infarction (P < 0.05) and among patients with a lower (< 45 years) age at infarction (P < 0.05). In patients who already underwent a previous CABG graft survival time was shortest in Hp 2-2 type (P < 0.05). Patients with a Hp 2-2 type more likely develop atherosclerotic lesions despite comparable serum lipid concentrations.

Adult↗