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PubMed1988

Assignment of human platelet GP2B (GPIIb) gene to chromosome 17, region q21.1-q21.3.

The platelet GPIIb-IIIa complex functions as a receptor for fibrinogen, fibronectin, and von Willebrand factor on activated platelets. This glycoprotein is a member of a broadly distributed family of structurally and immunologically related membrane receptors involved in cell-cell contact and cell-matrices interactions. GPIIb-IIIa is a heterodimer complex composed of GPIIb (the alpha subunit), which consists of two disulfide-linked heavy and light chains, and GPIIIa (the beta subunit), which is a single polypeptide chain. Congenital absence of platelet GPIIb-IIIa in Glanzmann's thrombasthenia results in a severe bleeding disorder characterized by defective platelet aggregation and failure of fibrinogen to bind to platelets. The gene coding for GPIIb was located on 17q21.1-17q21.3 as determined by in situ hybridization with a 2650-bp GP2B (GPIIb) cDNA probe prepared from human megakaryocytes.

Blood Platelets↗

PubMed1996

B-cell epitopes of varicella-zoster virus glycoprotein II.

B-cell epitopes of varicella-zoster virus glycoprotein II were mapped by means of solid phase ELISA, synthetic oligopeptides (constructed according to the Davison-Scott sequencing of the varicella-zoster virus genome) and sera from varicellae and herpes zoster patients. The individual pattern of antibody peptide binding varied considerably but at least 9 more reactive sites seemed discernible. A 31-mer-peptide corresponding to a hydrophilic segment of the glycoprotein (aa 417-447) was constructed. This peptide reacted with 2 out of 4 varicellae and 5 out of 9 zoster sera, respectively.

Adolescent↗

PubMed1996

Lack of platelet response to collagen associated with autoantibodies against glycoprotein (GP) Ia/IIa and Ib/IX leading to the discovery of SLE.

An increased bleeding time and a prolonged APTT (activated partial thromboplastin time) observed in a 48-year-old woman led to the discovery of SLE confirmed by immunological tests. Platelet function and analysis of membrane glycoproteins revealed an isolated impaired collagen induced platelet aggregation and allowed the detection of autoantibodies directed against GpIa/IIa and GpIb/IX.

Antigens, CD↗

PubMed2006

The glu298asp polymorphism in the nitric oxide synthase 3 gene is associated with the risk of ischemic stroke in two large independent case-control studies.

The search for genes involved in the pathogenesis of stroke has been highlighted as a field of needs. We followed the concept, that stroke represents a complex genetic disorder, and analyzed the contribution of 106 informative single nucleotide polymorphisms (SNPs) from 63 candidate genes for cardiovascular diseases for the risk of stroke. We conducted two independent case-control studies in two different German regions and recruited a total of 1,901 hospitalized stroke cases and 1,747 regional population controls. The smaller of both studies was used as the replication study. Multiplex PCR in combination with allele-specific hybridization was used for genotype determination. Descriptive statistics, permutations and multivariable logistic regression were used in the analyses. After permutation testing 5 SNPs, located in the nitric oxide synthase 3, the alpha 2 integrin, the interleukin 13, the selectin P and the chemokine receptor 2 genes, had a significant allele difference between cases and controls in the larger study. For one of these SNPs, the glu298asp polymorphism in the nitric oxide synthase 3 gene, an association with ischemic stroke was replicated in the second study and also in a combined analysis of both studies. This association was independent of age, gender, hypertension, diabetes and hypercholesterolemia in both studies. Using large sample sizes and a replication study approach, we found evidence for a role of a polymorphism in the nitric oxide synthase 3 gene in stroke onset.

Aged↗

PubMed2006

Butyrate-induced collagen biosynthesis in cultured fibroblasts is independent on alpha2beta1 integrin signalling and undergoes through IGF-I receptor cascade.

The potential role of butyrate to modulate cellular metabolism through integrin receptor led to evaluation of its effect on collagen biosynthesis in cultured fibroblasts. Confluent human dermal fibroblasts were treated with 2 mM and 4 mM of sodium butyrate (NaB) for 48 h. It was found that butyrate induced collagen biosynthesis and prolidase activity independently of alpha2beta1 integrin signaling. The expressions of both alpha2 and beta1 integrin subunits as well as integrin-induced activation of focal adhesion kinase (FAK) were not affected in the cells treated with NaB. Since insulin-like growth factor-I (IGF-I) is the most potent stimulator of collagen biosynthesis in fibroblasts, the effect of butyrate on IGF-I receptor (IGF-IR) expression was evaluated. It was found that the exposure of the cells to 4 mM butyrate contributed to a distinct increase in IGF-IR. It was accompanied by a parallel increase in the expression of Sos protein and MAP-kinases (ERK1, ERK2). The data suggests that butyrate-dependent stimulation of collagen biosynthesis in cultured human skin fibroblasts undergoes through IGF-IR signaling.

Blotting, Western↗

PubMed1990

Shear-induced platelet aggregation.

Two platelet mechanisms contribute to haemostasis and thrombosis. (1) Compounds such as thrombin activate glycoprotein IIb/IIIa; fibrinogen is the ligand. The cyclooxygenase pathway is involved and so this process is aspirin sensitive. (2) Shearing forces alone activate a different domain on glycoprotein IIb/IIIa; von Willebrand's factor is the ligand. This process is probably non-enzymatic and is aspirin insensitive. The prevention of shear-induced platelet activation may prove to be more rewarding therapeutically than inhibition of aspirin sensitive pathways.

Blood Circulation↗

PubMed1988

Immunological characterization of a membrane glycoprotein of chromaffin granules: its presence in endocrine and exocrine tissues.

A glycoprotein was isolated from detergent solubilized membranes of bovine chromaffin granules by high-performance liquid chromatography. Specific antisera raised against this glycoprotein reacted in one- and two-dimensional immunoblots with a heterogeneous component with a pI of 4.2-4.7 and Mr 100,000. The antiserum against bovine glycoprotein II cross-reacted with an analogous component in several species. The specific localization of glycoprotein II in chromaffin granules was established by density gradient centrifugation followed by immunoblotting. The antiserum, as shown by one- and two-dimensional immunoblotting, reacted with an analogous antigen in the posterior pituitary, in endocrine (anterior pituitary, parathyroid gland) and exocrine (parotid gland, pancreas) organs. In the pancreas the protein reacting with the antiserum was found in the membranes of zymogen granules. The results demonstrate for the first time that secretory vesicles of endocrine and exocrine tissues have at least one common antigen, i.e. the glycoprotein II. It seems likely that this protein is involved in a basic function common to all secretory vesicles.

Adrenal Medulla↗

PubMed1991

Prospects for the use of antagonists to the platelet glycoprotein IIb/IIIa receptor to prevent post-angioplasty restenosis and thrombosis.

Despite many advances since its inception in humans in 1977, coronary angioplasty continues to be limited by the problems of abrupt arterial closure and late restenosis. Excessive platelet deposition at the site of angioplasty undoubtedly plays an important role in the pathophysiology of both of these problems. Monoclonal antibodies and snake venom-derived or synthetic peptides directed against a common protein recognition sequence on the platelet glycoprotein IIb/IIIa receptor are currently in the early stages of preclinical and clinical testing and hold promise of preventing abrupt closure and restenosis by inhibiting platelet function. Whether any of these agents will eventually be commonly used in clinical practice will depend on their effects on the complex pathophysiology of these problems and on their safety profile when administered to patients who are likely to receive other antithrombotic medications and who are instrumented for coronary angioplasty.

Angioplasty, Balloon, Coronary↗

PubMed1995

Differential inhibition of platelet aggregation induced by adenosine diphosphate or a thrombin receptor-activating peptide in patients treated with bolus chimeric 7E3 Fab: implications for inhibition of the internal pool of GPIIb/IIIa receptors.

OBJECTIVES: This study sought to describe in detail the pharmacokinetics and pharmacodynamics of chimeric monoclonal 7E3 Fab (c7E3 Fab) and to compare platelet responses to adenosine diphosphate (ADP) and the 11-amino acid thrombin receptor-activating peptide (TRAP [SFLLRNPNDKY-NH2]) in patients undergoing elective coronary angioplasty. BACKGROUND: Inhibition of platelet aggregation with monoclonal antibody c7E3 Fab directed against glycoprotein (GP) IIb/IIIa has been shown to reduce ischemic complications after angioplasty and is being considered for treatment of other acute ischemic syndromes. METHODS: Patients undergoing elective coronary angioplasty received aspirin (325 mg orally), heparin (12,000 U intravenously) and a bolus of c7E3 Fab (0.25 mg/kg body weight). Surface GPIIb/IIIa receptor blockade and aggregation in response to 20 mumol/liter ADP, 5 micrograms/ml collagen and 7.5 and 15 mumol/liter TRAP were assessed. RESULTS: Surface GPIIb/IIIa receptor blockade by c7E3 Fab was 80% 2 h after injection and decreased to 50% at 24 h. Platelet aggregation in response to 20 mumol/liter ADP was inhibited by 73% at 2 h, and this inhibition decreased to 27% at 24 h. Platelet aggregation in response to 7.5 mumol/liter TRAP was inhibited by 53% at 2 h and 30% at 24 h. In contrast, aggregation in response to 15 mumol/liter TRAP was inhibited only 37% at 2 h and 10% at 24 h (p < 0.001 and p = 0.006, respectively vs. 20 mumol/liter ADP). Addition of exogenous c7E3 Fab to platelet-rich plasma led to more complete inhibition of 7.5 mumol/liter TRAP-induced aggregation. CONCLUSIONS: After c7E3 Fab treatment, inhibition of platelet aggregation depends on the agonist and can be overcome by increased thrombin activity but is restored if additional c7E3 Fab is added to block additional GPIIb/IIIa receptors. This phenomenon may be related to an internal pool of GPIIb/IIIa receptors joining the surface membrane and has implications concerning the duration of therapy with c7E3 Fab for patients with unstable angina or acute myocardial infarction.

Abciximab↗

PubMed2005

Variability in platelet aggregation following sustained aspirin and clopidogrel treatment in patients with coronary heart disease and influence of the 807 C/T polymorphism of the glycoprotein Ia gene.

A broad variability in patient response to dual antiplatelet treatment has been described during the first month of treatment. Data on platelet function profiles in patients on dual antiplatelet therapy for a more sustained period are limited. Whether gene sequence variations of the glycoprotein Ia/IIa receptor influence platelet aggregation in these patients is also unknown. The aim of this study was to characterize platelet aggregation profiles in patients on dual antiplatelet treatment (aspirin plus clopidogrel) for >1 month and to assess whether these may be influenced by the C807T polymorphism of the glycoprotein Ia gene. We included 82 patients, who were divided into 2 groups: carriers (CT + TT genotypes; n = 51) and noncarriers (CC genotype; n = 31) of the mutant T allele. Platelet aggregation was assessed using light transmittance aggregometry after stimuli with adenosine diphosphate (20 micromol/L), collagen (6 microg/ml), and epinephrine (20 micromol/L). A significant variability in the distribution of platelet aggregation was observed in the overall study population, as well as in carriers and noncarriers of the T allele. T allele carriers had increased platelet aggregation compared with noncarriers after stimuli with adenosine diphosphate, collagen, and epinephrine (p <0.05 for all platelet aggregation assays). Thus, platelet aggregation varied significantly in patients on long-term dual antiplatelet treatment and was increased in T allele carriers of the 807C/T polymorphism of the glycoprotein Ia gene. These findings may contribute to the increased ischemic risk observed in these patients.

Adult↗

PubMed2006

Assessment of the genetic component of hypertension.

BACKGROUND: Although genetic epidemiologic studies have suggested that several genetic variants increase the risk for hypertension, the genes that underlie genetic susceptibility to this condition remain to be identified definitively. We have now performed a large-scale association study to identify gene polymorphisms for reliable assessment of the genetic component of hypertension. METHODS: The study population comprised 4853 unrelated Japanese individuals, including 2818 subjects with hypertension (1677 men, 1141 women) and 2035 controls (1011 men, 1024 women). The genotypes for 150 polymorphisms of 128 candidate genes were determined with a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. RESULTS: Multivariable logistic regression analysis with adjustment for age, sex, body mass index, and the prevalence of smoking revealed that four polymorphisms (1648G-->A in ITGA2, -30G-->A in GCK, A-->G in SAH, and 1117C-->A in PTGIS) were significantly (P < .01) associated with hypertension. A stepwise forward selection procedure demonstrated that ITGA2, GCK, and PTGIS genotypes significantly affected the prevalence of hypertension. Combined genotype analysis of these polymorphisms yielded a lowest odds ratio of 0.47 for the genotypes of AA or AG for ITGA2, GA or AA for GCK, and CC for PTGIS, which were present in 1.1% and 2.0% of hypertensive and control individuals, respectively. CONCLUSIONS: These results suggest that the genotypes for ITGA2, GCK, and PTGIS may prove reliable for the assessment of the genetic component of hypertension. Determination of the combined genotypes for these genes may contribute to personalized prevention of this condition.

Aged↗

PubMed2006

Role of glycoprotein Ia gene polymorphisms in determining platelet function in myocardial infarction patients undergoing percutaneous coronary intervention on dual antiplatelet treatment.

Response variability to antiplatelet treatment has been described and the widespread use of acetylsalicylic acid (ASA) and clopidogrel requires clarification of the residual platelet reactivity (RPR). Various glycoprotein Ia (GpIa) polymorphisms have been investigated, but their influence on platelet reactivity in myocardial infarction (MI) patients undergoing percutaneous coronary intervention (PCI) on dual antiplatelet treatment is not still elucidated. Aim of this study was to evaluate the effect of C807T, G873A and T837C polymorphisms of GpIa on modulating platelet function in MI patients on dual antiplatelet treatment undergoing PCI. We measured platelet function by both a point-of-care assay (PFA100) and platelet-rich-plasma aggregation in 289 MI patients undergoing PCI and receiving dual antiplatelet treatment. Our data show that C807T/G873A polymorphisms, but not T837C, are associated with higher platelet reactivity. Carriers of the 807T/873A allele had significantly higher platelet aggregation values after arachidonic acid (AA) and collagen stimuli and, even if they did not reach the statistical significance, after 2 and 10 microM ADP stimuli; 807T/873A allele carriers had also significantly shorter closure times on PFA100/epinephrine membranes. At the multiple analyses, C807T/G873A polymorphisms resulted an independent risk factor for RPR defined by both AA induced platelet aggregation (OR=3.0, 95%CI 1.17-7.89, p=0.022) or by PFA100/epinephrine (OR=4.1, 95%CI 1.53-10.89, p=0.005). In conclusion, this study shows the 807T/873A allele of the GpIa gene is an independent risk factor for the RPR on dual antiplatelet treatment, and extends, in a larger acute coronary syndrome population, the observation that the 807T/873A allele is associated with higher platelet reactivity.

Adult↗

PubMed2006

Antigen-specific accumulation of naïve, memory and effector CD4 T cells during anterior uveitis monitored by intravital microscopy.

Uveitis is an immune-mediated ocular disease and a leading cause of blindness. We characterized a novel model of uveitis with intravital microscopy. Transfer of ovalbumin-specific T cells from DO11.10 spleen to BALB/c recipients and subsequent challenge with ovalbumin in the anterior chamber of the eye resulted in anterior uveitis. Antigen-specificity was verified by injection of irrelevant antigen and transfer of T cells with a different specificity. Subsets of CD4 T cells, including naive (DO11.10 RAG(-/-)) and in vitro-activated Th2 effector CD4 T cells, infiltrated anterior segment tissues early in the inflammation. Memory-like CD44(high) CD4 T cells from unprimed transgenic mice and in vitro-activated Th1 effector CD4 T cells accumulated to larger numbers than naive or Th2 effector cells at 48 and 72 h. Of these, the alpha(2)-integrin+CD4 unprimed T cells entered the eye more efficiently, and antibody to alpha(2)-integrin markedly inhibited the inflammatory response. Intravital microscopy revealed the early arrival and antigen-specific accumulation of CD4 T cells in inflamed tissue and should be helpful in understanding T cell migration to other organs.

Animals↗

PubMed2006

Association of platelet glycoprotein Ia polymorphism with minor increase of risk for oral cancer.

AIMS: In light to association of increased platelet glycoprotein Ia (GPIa) expression with tumor invasion and metastasis in several types of cancer, we investigated the possible contribution of a common polymorphism (C807/T807), affecting the GPIa gene expression, in the development of oral cancer. METHODS: DNA samples of 110 patients with oral cancer and 114 healthy controls were examined by allele-specific polymerase chain reaction followed by electrophoretic analysis. RESULTS: The mutant T807 allele homozygotes were significantly increased in the group of patients compared to the control group (P < 0.001). Furthermore, significantly increased frequency of mutant alleles compared to controls was observed in the subgroup of patients with a positive history for cancer (P < 0.01). CONCLUSIONS: The obtained results indicate that the C807/T807 polymorphism is indeed a genetic predisposing factor which contributes to increased risk for oral cancer.

Alleles↗

PubMed2006

Lack of association between the platelet glycoprotein Ia C807T gene polymorphism and coronary artery disease: a meta-analysis.

BACKGROUND: The platelet-collagen receptor, glycoprotein (GP) la/lla plays a crucial role in the adhesion of platelets to fibrillar collagen, an event contributing to the pathogenesis of thrombosis. The C807T polymorphism of the GPla gene is considered a genetic marker of the platelet GPla/lla density. The importance of the GPla gene C807T polymorphism as a genetic risk factor for coronary artery disease (CAD) remains controversial. To assess this association, we performed a meta-analysis of published data. METHODS: A comprehensive meta-analysis of 19 studies, with a total sample of 13835 subjects using random effects models. RESULTS: The C versus T allele contrast gave an OR of 0.998 with 95% Cl 0.937-1.064. Similarly, comparing the C homozygotes with the T homozygotes, the CC genotype versus the others and the TT genotype versus the rest, no evidence of any gene-disease association was obtained. Furthermore, the meta-regression analysis did not disclose any variable that could modify the role of this polymorphism in the development of CAD. CONCLUSION: Our findings support the view that C807T polymorphism of the GPla gene is not a significant risk factor for CAD, either alone or in combination with other major cardiovascular risk factors.

Coronary Artery Disease↗

PubMed2006

Oral ingestion of cow's milk immunoglobulin G stimulates some cellular immune systems and suppresses humoral immune responses in mouse.

Four-week-old male C3H/HeN mice were bred with diets consisting of ovalbumin alone (OVA, control diet) or mixtures of OVA and cow's milk immunoglobulin G (IgG-added diets) as a protein source for 4 or 5 weeks, and both the cellular and humoral immune properties of the mice were investigated. The number of interleukin (IL)-12+CD11b+ cells in spleens and the formation of superoxide by peritoneal macrophages were higher in mice given the IgG-added diet than in those given the control diet. The number of natural killer cells in Peyer's patches or spleens and the cytotoxic activity of spleen cells toward an erythroleukemia cell line, K562, were also higher in mice given the IgG-added diet. In contrast, the numbers of interferon-gamma+CD4+ and IL-4+CD4+ cells in Peyer's patches or spleens and the levels of total or OVA-specific intestinal IgA and serum IgG were significantly lower in mice given the IgG-added diet than in those given the control diet. In addition, the number of cells expressing CD19 in spleens was significantly higher in mice given the IgG-added diet. These results indicate that oral ingestion of cow's milk IgG may stimulate some innate cellular immune systems, while suppressing humoral adaptive immune responses in the mouse.

Administration, Oral↗

PubMed2006

Genetic polymorphisms of platelet glycoprotein Ia and the risk for premature myocardial infarction: effects on the release of sCD40L during the acute phase of premature myocardial infarction.

OBJECTIVES: The aim of this research was to evaluate the effect of genetic polymorphisms C807T and G1648A of platelet glycoprotein Ia (GPIa), on the risk for myocardial infarction (MI) and on the release of soluble CD40 ligand (sCD40L) during the acute phase of MI and one year after the event. BACKGROUND: C807T and G1648A polymorphisms affect the density of GPIa on platelet surface, but their effect on the risk for MI and the release of sCD40L is unknown. METHODS: The study population consisted of 219 patients with premature MI and 389 controls. One year after the event, 67 patients and 232 controls were recalled for the follow-up study. RESULTS: The risk for MI in 807TT was 2.296 (95% confidence interval [CI]: 1.187 to 4.440) p < 0.05 versus CC + CT, 2.269 (95% CI: 1.085 to 4.745) p < 0.05 versus CC, and 2.135 (95% CI: 1.080 to 4.219) p < 0.05 versus CT. During the acute phase of MI, sCD40L was higher in 807CT + TT compared with 807CC (p < 0.01), an effect persisting after one year (p < 0.01). The carriage of 807T allele was an independent predictor for sCD40L during the acute phase of MI (beta = 9.442 [standard error (SE): 2.526], p = 0.001) and in the same patients one year later (beta = 8.282 [SE: 2.044], p = 0.001). In healthy individuals, 807T allele was associated with higher sCD40L levels compared with 807CC (p < 0.05), only among those with von Willebrand factor greater than or equal to median. CONCLUSIONS: Genetic polymorphism C807T increases the risk for premature MI. 807T allele is an independent predictor for sCD40L levels during the acute phase of premature MI as well as one year after the event, while it is associated with elevated sCD40L levels in healthy subjects, only in the presence of high von Willebrand levels.

CD40 Ligand↗

PubMed2005

Fractalkine-upregulated milk-fat globule EGF factor-8 protein in cultured rat microglia.

Fractalkine is the only known member of the CX(3)C-chemokine family, and so is its receptor CX(3)CR1. Fractalkine, typically is expressed by neurons where it is inserted in the plasma membrane ("chemokine on a stalk"). It can, however, be clipped off by a specific enzyme and diffuse into the extracellular space. CX(3)CR1 is primarily expressed by microglia, the phagocytes of the brain. This study was aimed at studying gene expression changes in cultured rat microglia upon fractalkine stimulation using gene chip technology. Six genes turned out to be upregulated, amongst which milk-fat globule EGF factor-8 protein (MFG-E8) was the most surprising, but also the most revealing one. We hypothesize that it serves as a bridging molecule between apoptotic cells (neurons) and microglia. Since the docking to microglia is, in part, mediated by members of the integrin family, six of these molecules have been-post hoc-included in real-time PCR confirmations of chip results. Two of them-integrin alpha(2) and integrin beta(5)-were upregulated as well. These data provide a much closer look into molecular mechanisms involved in apoptosis of neurons and their removal by microglia.

Animals↗