Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Biological and clinical significance of haptoglobin polymorphism in humans. 934 38

Globin-free hemin and certain hemoproteins, predominantly hemoglobin, are active triggers of low-density lipoprotein (LDL) peroxidation, a contributing cause of atherosclerosis. The role of the plasma heme-binding protein, hemopexin, in protecting apolipoprotein B and LDL lipids from oxidation triggered by either hemin or hemoglobin in the presence of low amounts of H2O2, was investigated at physiological pH and temperature. Significantly, hemopexin prevented not only hemin-mediated modification of LDL but also LDL peroxidation induced by hemoglobin, both by met and oxy forms. Analysis of the data revealed that the rate of heme transfer from methemoglobin to hemopexin was highly dependent upon temperature: only minimal heme transfer occurred at 20 degrees C, whereas at the physiological temperature of 37 degrees C, heme transfer was rapid, within the lag phase of LDL oxidation, regardless of the presence or absence of H2O2. Heme did transfer to hemopexin from oxyhemoglobin as well, but only in the presence of H2O2. The proposed mechanism of the inhibition of oxyhemoglobin oxidative reactivity by hemopexin involves peroxidation of oxyhemoglobin (Fe(II)) to ferrylhemoglobin (FeIV), followed by a comproportionation reaction (FeIV+FeII-->2FeIII), yielding methemoglobin (FeIII) from which heme is readily transferred to hemopexin. Taken together, the data demonstrate that hemopexin can act as an extracellular antioxidant against hemoglobin-mediated damage in inflammatory states, which is especially important when haptoglobin is depleted or absent.
 ...
PMID:Role of hemopexin in protection of low-density lipoprotein against hemoglobin-induced oxidation. 885 48

Haptoglobin is a hemoglobin-binding antioxidant showing a genetic polymorphism with three types: Hp 1-1, Hp 2-1, and Hp 2-2. The Hp 2-2 type has been associated with an increased risk of atherosclerosis. We investigated vitamin C metabolism in vivo and in vitro according to haptoglobin type in a study group of 135 healthy volunteers. Serum vitamin C concentrations were associated with haptoglobin type, showing lowest values in serum from Hp 2-2 subjects (P < 0.01). Renal threshold for L-ascorbic acid was within the normal range and metabolization to oxalate was not different among haptoglobin-type groups. Serum concentrations of other endogenous antioxidants (uric acid, bilirubin, albumin, ceruloplasmin, and total antioxidative status) were not different among haptoglobin-type groups. In vitro experiments showed a lower stability of L-ascorbic acid in blood from subjects with the Hp 2-2 type (P < 0.01). L-Ascorbic acid depletion in vitro was inversely related to haptoglobin concentration (r = -0.738). The results of this study indicate a higher rate of L-ascorbic acid oxidation in Hp 2-2 carriers because they have less protection against hemoglobin-iron driven peroxidation.
 ...
PMID:Effect of haptoglobin on the metabolism of vitamin C. 928 Jan 80

Serum lipoproteins including lipoprotein(a), Lp(a), are emerging as possible biological markers for cerebrovascular disease. Existing data on Lp(a) and serum lipids levels following acute ischemic stroke (AIS) are however equivocal. To determine whether serum Lp(a) and other lipid levels obtained within 24 h of acute ischemic stroke onset changed over the ensuing 4 weeks and whether these levels are related to an acute phase response, acquired nutritional deficiency, and neurovascular data, we conducted repeated measurement analyses among 19 subjects (mean age 65.0 +/- 12.1 years; 32% women) presenting with AIS (evaluated within 9.7 +/- 12.7 h). Eleven of the subjects had a moderate-to-severe stroke, defined by NIH stroke severity scale, and seven patients had a large cerebral infarction. Seven serial measurements of Lp(a), total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, and other lipoproteins, major acute phase reactants and albumin levels were collected for each subject over 4 weeks. The mean initial levels, (mg/dl), of total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, Lp(a), apolipoproteins A-I and B were: 225 +/- 57.6, 154 +/- 56.0, 40 +/- 10.4, 181 +/- 93.7, 52 +/- 28.6, 130 +/- 24.6, and 141 +/- 46.1, respectively. There were no significant changes in mean serum lipid, apolipoprotein or Lp(a) levels over the 4-week study period, analyzed by a random effects model to test for time trend. In addition, there were no significant changes in established acute phase or nutritional markers (C-reactive protein, alpha 1-glycoprotein, haptoglobin or serum albumin). Our findings suggest that serum lipid, apolipoprotein and Lp(a) levels remain stable following AIS, consistent with the absence of acute phase response or nutritional deficiency.
Atherosclerosis 1998 Aug
PMID:Lipid and lipoprotein levels remain stable in acute ischemic stroke: the Northern Manhattan Stroke Study. 971 47

The haptoglobin allele frequencies and the phenotype distribution were determined in 741 male Caucasian workers, aged 35 to 59 years. The association of the haptoglobin polymorphism with various clinical and biochemical parameters was investigated. Furthermore a possible interaction with the apo E polymorphism on lipid and lipoprotein traits was analysed. The frequency of Hp1 and Hp2 was found to be 0.401 and 0.599, respectively. The observed distribution of Hp types (Hp 1-1, 15.5%; Hp 2-1, 49.3%; Hp 2-2, 35.2%) was in Hardy-Weinberg equilibrium. Age, body mass index, smoking, alcohol intake and blood pressure were comparable between the three Hp groups. Subjects with Hp 2-2 had significantly higher serum total and free cholesterol concentration compared to those in other haptoglobin types (P = 0.006 and P = 0.003). Similarly, apo B levels were significantly higher among Hp 2-2 individuals (P = 0.02). No significant differences were demonstrated between the Hp phenotypes in HDL cholesterol, apo A-I, apo E, Lp(a), cholesteryl esters, fibrinogen and C-reactive protein concentrations, although for the latter an increase was noticed in Hp 2-2. The effects of Hp type and apo E type on Lp(a) and on free cholesterol levels were found to be significantly multiplicative, with the highest free cholesterol values observed in subjects having Hp 2-2 and the apo epsilon4 allele. Significantly lower Lp(a) levels were observed in individuals carrying Hp 1-1 and an epsilon2 allele than in subjects without the epsilon2 allele. In conclusion, haptoglobin polymorphism may play an important role in the regulation of lipoprotein metabolism and could contribute to the risk of coronary heart disease. Larger samples are needed to clarify the clinical relevance of the gene-gene (Hp-apo E) interaction on lipids and lipoproteins.
Atherosclerosis 1999 Apr
PMID:Associations between haptoglobin polymorphism, lipids, lipoproteins and inflammatory variables. 1021 68

Treatment with a chimeric mAb to TNF-alpha has been shown to suppress inflammation and improve patient well-being in rheumatoid arthritis (RA), but the mechanisms of action of such treatment have not been fully explored. Here we show that in vivo administration of anti-TNF-alpha Ab, using a longitudinal analysis, results in the rapid down-regulation of a spectrum of cytokines, cytokine inhibitors, and acute-phase proteins. Marked diurnal variation in the serum levels of some of these were detected. These results were consistent with the concept of a cytokine-dependent cytokine cascade, and the degree of clinical benefit noted after anti-TNF-alpha therapy is probably due to the reduction in many proinflammatory mediators apart from TNF-alpha, such as IL-6, which reached normal levels within 24 h. Serum levels of cytokine inhibitors such as soluble p75 and p55 TNFR were reduced as was IL-1 receptor antagonist. Reductions in acute-phase proteins occurred after serum IL-6 fell and included serum amyloid A, haptoglobin, and fibrinogen. The latter reduction could be of importance, as it is a risk factor for atherosclerosis, which is augmented in RA patients.
 ...
PMID:Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis. 1041 55

Inflammatory phenomena at sites of atherosclerotic plaques are increasingly thought to be major determinants of the progression and clinical outcome of atherosclerotic disease. Therefore, attention is being paid to systemic markers/mediators which may reflect the inflammatory activity in the plaques. This study evaluates the pattern of the main proinflammatory cytokines tumor necrosis factor-alpha (TNFalpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6), their soluble receptors/antagonist, and a variety of inflammatory markers, in patients with peripheral arterial disease (PAD). Eight patients with PAD suffering from claudicatio intermittens (CI), eight with critical limb ischemia (CLI) and eight controls (C) were studied. Blood samples were collected at baseline in all groups and. for C and CI, immediately after and 4 h after a 30-min treadmill test. Baseline: no differences in cytokine plasma levels were detected among the three groups. In contrast, soluble receptors of TNF (type I and II) and of IL-6, and IL-1beta receptor antagonist (IL-1ra) were increased in CI and CLI patients, as compared to C. Of note, IL-Ira correlated with the occurrence and stage of the disease in a highly significant proportion of the patients, reaching a predictive value for the disease of P < 0.0001. The opposite trend was observed for the soluble receptor of IL-1beta. Notably, in the patients no alterations could be found in white blood cell counts, expression of CD11c adherence molecule by circulating monocytes or, in vitro. O2- release from zymosan-activated neutrophils. Moreover, plasma levels of platelet activating factor (PAF), of neutrophil elastase and of the acute phase reactants C-reactive protein (CRP) and alpha1-acid glycoprotein were not found to be significantly altered. In contrast, the acute-phase proteins alpha1-antitrypsin (alpha1AT) and haptoglobin (HG) were found to be increased. Effect of treadmill: IL-1beta and TNFalpha remained at baseline levels following exercise, and IL-6 dropped to undetectable levels. Among cytokine antagonists, again the most relevant changes concerned the IL-1ra, which was significantly increased immediately after the treadmill test, both in CI and C, and returned to baseline levels after 4 h. In contrast, soluble TNFalpha, IL-1beta and IL-6 receptors, PAF, and the other markers of leukocyte activation were not found to be altered. Soluble TNFalpha and IL-6 receptors were shown to inhibit the biological effects of their ligands. Similarly, IL-1ra and the acute phase proteins alpha1AT and HG have been reported to exert anti-inflammatory functions. The increased plasma levels of these agents, together with low levels of inflammatory cytokines and other pro-inflammatory mediators such as PAF and alpha1-acid glycoprotein, appear to draw an undescribed picture, so far, of upregulation of a composite systemic anti-inflammatory mechanism in atherosclerotic patients. IL-1ra appears to be a reliable marker of the state of activation of this mechanism. These results may provide a basis for developing new insights into the pathogenesis of the atherosclerotic disease.
Atherosclerosis 1999 Jul
PMID:Atherosclerosis and inflammation. Patterns of cytokine regulation in patients with peripheral arterial disease. 1042 95

Serum total sialic acid (S-TSA) is a recently identified risk marker for atherosclerosis and cardiovascular mortality. The purpose of this study was to evaluate the influence of three sialic acid rich glycoproteins (orosomucoid, haptoglobin, and alpha1-antitrypsin) on the relationship between S-TSA and carotid atherosclerosis. The mean S-TSA was 0.045 g/l higher among cases than controls (P<0.001) in 310 45-64 year-old male and female pairs of carotid atherosclerosis cases and disease-free controls from the Atherosclerosis Risk in Communities (ARIC) Study. Also mean serum levels of the glycoproteins were significantly higher in cases compared to controls. In a conditional multiple logistic regression model with the glycoproteins as independent variables, orosomucoid was correlated most strongly with case control status. However, when incorporated into the mathematical model, S-TSA not only contributed additional information as to the risk of atherosclerosis; none of the three glycoproteins contributed further once S-TSA had been accounted for. Thus, some other source of serum sialic acid or variations in the degree of sialylation of glycoproteins may be essential for understanding the relation between S-TSA and atherosclerosis.
Atherosclerosis 1999 Sep
PMID:Serum sialic acid and sialoglycoproteins in asymptomatic carotid artery atherosclerosis. ARIC Investigators. Atherosclerosis Risk in Communities. 1048 88

Haptoglobin (Hp) 2-2 phenotype is a genetic risk factor in coronary atherosclerosis. In this study, haptoglobin phenotypes were determined in 141 patients with peripheral arterial occlusive disease (PAOD) and compared to a reference population (n = 1000). The relative Hp1 allele frequency was decreased among PAOD patients (0.294 vs. 0.403 for the reference population, P < 0.01) due to an overrepresentation of the Hp 2-2 phenotype (50%, odds ratio 1.82 (95% C.I. 1.28-2.60), P < 0.001). This finding was even more pronounced in non-diabetic and in non-smoking PAOD patients (Hp1 allele frequencies: 0.265 and 0.228, respectively). Serum lipids, inflammatory parameters, and blood pressure levels were comparable among the Hp phenotypes, but serum levels of the antioxidant vitamin C were lower in Hp 2-2 patients than in patients with another phenotype (P < 0.05). In PAOD patients with severe atherosclerotic lesions, maximal walking distance of patients carrying a Hp 2-2 phenotype (225-525 m) exceeded that of other Hp phenotypes (50-242 m) (interquartile ranges) (P < 0.05). The findings demonstrate that, despite an increased risk for developing PAOD, the Hp 2-2 phenotype is associated with a longer maximal walking distance which might be attributed to the earlier reported in vitro angiogenic properties of the Hp 2-2 molecule.
Atherosclerosis 1999 Aug
PMID:Haptoglobin polymorphism and peripheral arterial occlusive disease. 1048 55

Apolipoprotein E (ApoE) plays an important role in cholesterol and triglyceride metabolism, being one of the major structural components of chylomicrons and very low density lipoprotein (VLDL) remnants. ApoE functions as a ligand in the receptor-mediated uptake of these remnants from the blood by the liver. A variant form of ApoE, apolipoprotein E*3-Leiden, shows reduced affinity for the low density lipoprotein (LDL) receptor, and results in the dominant expression of type III hyperlipoproteinemia. Two-dimensional electrophoresis (2-DE) has been used to characterise protein expression in serum samples from control and transgenic mice expressing the human ApoE*3-Leiden mutation, fed a cholesterol-rich diet, and transgenic mice fed a normal diet. For the identification of proteins, single silver-stained spots were excised from the 2-DE gels and subjected to in-gel enzymatic digestion. Extracted peptides were analysed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). This proteomic approach has enabled the ApoE*3-Leiden variant to be positioned in a 2-DE separation of serum proteins, and has identified changes in the expression of haptoglobin, indicating that this protein may provide a marker for the potential onset of atherosclerosis.
 ...
PMID:Phenotyping apolipoprotein E*3-leiden transgenic mice by two-dimensional polyacrylamide gel electrophoresis and mass spectrometric identification. 1093 69


<< Previous 1 2 3 4 5 6 7 Next >>