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PubMed2005

Comparison of enoxaparin versus heparin during elective percutaneous coronary intervention performed with either eptifibatide or tirofiban (the ACTION Trial).

Limited data are available with regard to the pharmacodynamics and safety of combining enoxaparin with glycoprotein IIb/IIIa inhibition during elective percutaneous coronary interventions (PCIs). We randomized 200 patients to receive open-label enoxaparin (0.75 mg/kg intravenous bolus) or unfractionated heparin (60 U/kg intravenous bolus) and eptifibatide or tirofiban during PCI. This yielded 4 groups of combination therapy (50 patients/group). The first 10 patients per group had anti-Xa activity and inhibition of platelet aggregation measured at baseline, and at 5 minutes, 10 minutes, 4 hours, and 24 hours. All patients received aspirin and clopidogrel therapy before PCI. Patients who received enoxaparin and heparin achieved therapeutic peak anti-Xa activity observed shortly after drug administration. At 4 hours, a differential anticoagulant effect was observed, with patients who received enoxaparin having a more gradual decrease in anti-Xa activity. Patients who received eptifibatide achieved >80% inhibition of platelet aggregation soon after initiation of therapy more often than did those who received tirofiban. Type of heparin did not affect inhibition of platelet aggregation. Compared with patients who received heparin, periprocedural myocardial infarction and bleeding events occurred less frequently among those who received enoxaparin (14% vs 8% and 10% vs 5%); however, these differences were not statistically significant. Three cases of intraprocedural thrombus occurred among patients who received enoxaparin. Two patients received concomitant tirofiban therapy. Compared with unfractionated heparin, similar levels of anticoagulation and platelet inhibition are achieved with enoxaparin when concomitant therapy with eptifibatide or tirofiban is used during elective PCI, without an observed increase in early bleeding events or periprocedural ischemic complications.

Aged↗
PubMed2005

TGF-beta1-mediated activations of c-Src and Rac1 modulate levels of cyclins and p27(Kip1) CDK inhibitor in hepatoma cells replated on fibronectin.

Integrin-mediated cell adhesion transduces signals to regulate actin cytoskeleton and cell proliferation. While understanding how integrin signals cross-talk with the TGF-beta1 pathways, we observed lamellipodia formation and cyclin regulation in Hep3B cells, following TGF-beta1 treatment. To answer if integrin signaling via actin organization might regulate cell cycle progression after TGF-beta1 treatment, we analyzed cross-talk between the two receptor-mediated pathways in hepatoma cells on specific ECMs. We found that basal and TGF-beta1-mediated activation of c-Src and Rac1, expression of cyclins E and A, and suppression of p27Kip1 were significant in cells replated on fibronectin, but not in cells on collagen I, indicating a different integrin-mediated cellular response to TGF-beta1 treatment. Levels of tyrosine phosphorylation and actin-enriched lamellipodia on fibronectin were also more prominent than in cells on collagen I. Studies using pharmacological inhibitors or transient transfections revealed that the preferential TGF-beta1 effects in cells on fibronectin required c-Src family kinase activity. These observations suggest that a specific cross-talk between TGF-beta1 and fibronectin-binding integrin signal pathways leads to the activation of c-Src/Rac1/actin-organization, leading to changes in cell cycle regulator levels in hepatoma cells. Therefore, this study represents another mechanism to regulate cell cycle regulators when integrin signaling is collaborative with TGF-beta1 pathways.

Actins↗
PubMed2006

Pre-adsorbed type-I collagen structure-dependent changes in osteoblastic phenotype.

Type-I collagen is the most abundant extracellular matrix in bones and modulates various functions of osteoblasts. We prepared two different structures of type-I collagen on tissue culture grade polystylene (TCPS) surfaces, one is feltwork structure of filamentous molecules from acid solutions (ACs) and the other is network structure of fibrils from neutral solutions (NCs), to examine effects of the structures on the maturation process of osteoblast-like cells. No significant differences of cell proliferation were observed between TCPS and ACs, but NCs delayed the proliferation. In initial cell attachment, the cells on ACs had tense lamellipodia with sharp tips, while those on NCs had loose lamellipodia. No detectable differences in levels of expressed integrin alpha2- and alpha5-subunits were observed between the structures. Although the matrix mineralization in NCs was also delayed in comparison with TCPS and ACs, fully mineralized levels in NCs were the same as those of TCPS and ACs. In addition, although we examined the effects of densities of pre-adsorbed collagen molecules on osteoblast maturation, the effects were less serious than those of the structures. This study suggests that the structures of collagen affect proliferation and mineralization of osteoblast-like cells.

Animals↗
PubMed2006

Platelet glycoprotein polymorphisms: risk, in vivo expression and severity of atherothrombotic stroke in Chinese.

BACKGROUND: Polymorphisms in platelet glycoprotein (GP) receptors Ia, Ib and IIIa may be heritable risk factors for platelet-dependent thrombosis leading to death. The precipitation of stroke by occlusive thrombi has led to the investigation of the platelet surface GP receptors, that are involved in critical steps in the activation of platelets. Three polymorphisms in the GP Iba gene and one in each of GPIIIa, GP Ia were selected based on the evidence of functional effects on structure or expression as candidates for risk. We also determined whether these polymorphisms were associated with in vivo expression levels of platelet GP receptors and the severity of the neurological deficit. METHODS: A Chinese hospital-based case-control study was conducted with 119 cases of atherothrombotic stroke and 166 age and sex matched controls. Genotyping was performed on lymphocyte DNA by standard methods and platelet GP expression levels were measured by flow-cytometry. RESULTS: Allele and genotype frequencies of the GP receptor polymorphisms differ considerably between ethnic populations. We found the D allele of the GP Iba VNTR polymorphism was significantly associated with atherothrombotic stroke in our Chinese cohort, however we did not find a relationship among these polymorphisms, the expression levels of GP receptors and severity of the neurological deficit. CONCLUSIONS: In our Chinese cohort the D allele of the GP Iba VNTR polymorphism is associated with atherothrombotic stroke. The number of VNTR repeats alters the length of amino acid sequence, which might affect the structure and function of this receptor.

Adult↗
PubMed2004

Platelet GPIaC807T polymorphism is associated with negative outcome of sudden hearing loss.

To determine the relevance of inherited prothrombotic risk factors in sudden hearing loss, we investigated 85 patients with sudden hearing loss of >/= 60 dB for the presence of inherited prothrombotic risk factors. The FV G1691A, FII G20210A, GPIa C807T, GPIIIa PIA1/A2, PAI-1 4G/5G, t-PA Alu repeat ID, MTHFR C677T and CBS 844ins68 genotypes were investigated. Allele frequencies found in patients were compared to those of 85 healthy control subjects of the same ethnic background using Chi-squared and odds-ratio analysis. The frequency of the GPIa807T allele was significantly elevated in patients compared to controls. In addition, allele frequency and genotype distribution of GPIa was significantly elevated in the patient group without recovery after 3 months of sudden hearing loss onset. Allele frequencies of all other prothrombotic risk factors investigated here did not differ from those of the control subjects. The single-nucleotide polymorphism of GPIa C807T seems to play a role as a prognostic factor in recovery from sudden hearing loss.

Adolescent↗
PubMed2004

Platelet glycoprotein Ia C807T, Ib C3550T, and IIIa Pl(A1/A2) polymorphisms and ischemic stroke in young Taiwanese.

Platelet plays a pivotal role in the pathogenesis of thrombotic cardiovascular diseases. Recently, the polymorphism of platelet glycoprotein (GP) genes has been reported to be associated with an increased risk for ischemic stroke. The purpose of this study is to evaluate the association between platelet GP genetic variants and ischemic stroke in young Taiwanese. We conducted a case-control study in 157 young ischemic stroke patients recruited between September 2001 and March 2003 and 157 age- and sex-matched controls. The genotypes of platelet GP Ia C807T, GP Ib C3550T, and GP IIIa Pl(A1/A2) polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism. Student's t-test, chi-square test, and logistic regression modeling were used for data analyses. The GP Ia C807T CC, CT and TT genotype frequencies were similar between patients (50.3%, 43.9%, 5.7%) and controls (53.5%, 38.9%, 7.6%; p=0.58). There were no significant differences in GP Ib C3550T CC and CT genotype distributions between patients (91.1%, 8.9%) and controls (91.7%, 8.3%; p=0.84). Of all subjects, none carries GP IIIa Pl(A2) mutation. In conclusion, platelet GP Ia C807T and GP Ib C3550T polymorphisms in our population are less common compared with Caucasians, and GP IIIa Pl(A1/A2) genetic mutation is not found, and all of them are not associated with ischemic stroke in young Taiwanese.

Adolescent↗
PubMed2005

Role of thrombophilic gene polymorphisms in branch retinal vein occlusion.

OBJECTIVE: Branch retinal vein occlusion (BRVO) is a common cause of severe visual loss. Numerous risk factors, including arterial hypertension, diabetes mellitus, and arteriosclerosis, have been identified. Gene polymorphisms affecting hemostasis may also play a role in the pathogenesis of BRVO. The present study was therefore done to determine the prevalence of genetic polymorphisms in factors implicated in hypercoagulability among patients with BRVO. DESIGN: Retrospective case-control study. PARTICIPANTS: The study cohort consisted of 294 patients with BRVO and 294 control subjects, matched for age and gender. METHODS: Determination of genotypes was done by allele-specific digestion of polymerase chain reaction products, or by 5' exonuclease assay (TaqMan). MAIN OUTCOME PARAMETERS: Genotypes of factor V R506Q (factor V Leiden), prothrombin 20210G>A, fibrinogen beta -455G> A, factor XII (FXII) 46C>T, and ITGA2 807C>T (platelet glycoprotein Ia [GPIa] 807C>T) and ITGB3 L59P (platelet GPIIIa PlA1/PlA2) polymorphisms. RESULTS: Genotype distributions of the investigated gene polymorphisms did not differ significantly between patients and control subjects. In contrast, significantly increased prevalences of arterial hypertension and hypercholesterolemia were found among patients with BRVO. In a logistic regression analysis, the presence of arterial hypertension was associated with an odds ratio (OR) of 2.32 (95% confidence interval [CI], 1.62-3.32), whereas hypercholesterolemia yielded an OR of 2.54 (95% CI, 1.74-3.70) for BRVO. CONCLUSION: Our data indicate that the prevalences of the investigated gene polymorphisms do not differ significantly in patients with BRVO and control subjects. This suggests that these polymorphisms are not major risk factors for BRVO.

Adult↗
PubMed2005

PTH-related protein enhances LoVo colon cancer cell proliferation, adhesion, and integrin expression.

Parathyroid hormone-related protein (PTHrP) has been localized in human colon cancer tissue and cell lines. Tumor cell adhesion to extracellular matrix (ECM) proteins plays a major role in the invasion and metastasis of tumor cells, and is mediated via integrin subunits. The LoVo human colon cancer cell line was used as a model system to study the effects of PTHrP on cell proliferation and adhesion to ECM proteins found in normal liver. Clones of LoVo cells engineered to overexpress PTHrP by stable transfection with a PTHrP cDNA showed enhanced cell proliferation vs. control (empty vector-transfected) cells. PTHrP-overexpressing cells also showed significantly higher adhesion to collagen type I, fibronectin, and laminin, and enhanced expression of the [symbol: see text] integrin subunits. These results indicate that PTHrP may play a role in colon cancer invasion and metastasis by increasing cell proliferation and adhesion to the ECM via upregulation of proinvasive integrin expression.

Acid Phosphatase↗
PubMed1998

Endothelial cell integrin laminin receptor expression in multiple sclerosis lesions.

Laminin, a major glycoprotein component of vessel basement membranes, is recognized by beta1- and beta3-integrins expressed on endothelial cells. To determine how endothelial cell integrins might function in multiple sclerosis (MS) lesions, integrin laminin receptors and laminin were analyzed in central nervous system samples from MS patients and controls by immunohistochemistry. In active MS lesions, endothelial cell VLA-6 and beta1 subunits were decreased compared to controls whereas alpha(v) subunit and VLA-1 were increased. In chronic inactive lesions beta1, VLA-6 and alpha(v) were the same as controls but VLA-1 remained increased. Alpha3 subunit was constant in all samples. By immunoelectron microscopy VLA-1, VLA-6, beta1, and laminin were distributed throughout endothelial cells; alpha(v) was adjacent to and on luminal surfaces; alpha(v) and VLA-1 were on intercellular junctions. These results indicate distinct regulation and functions of these integrins in different lesion stages. In active lesions decreased endothelial cell beta1/VLA-6 could result in their detachment from laminin thereby facilitating leukocyte transvascular migration and blood-brain barrier breakdown. Alpha(v) and VLA-1 on intercellular junctions may participate in re-establishing vessel integrity after leukocyte migration. Luminal surface alpha(v) also likely binds intraluminal ligands and cells. In chronic inactive plaques persistently elevated endothelial cell VLA-1 correlates with long-standing endothelial cell and blood-brain barrier dysfunction.

Adolescent↗
PubMed2001

Patterns of integrin expression in a human mandibular explant model of osteoblast differentiation.

Cell-matrix interaction is crucial in regulating osteoblast differentiation and function. These interactions are themselves regulated, at least in part, by integrins. Although there are some data from mammalian models, few studies have compared integrin expression at different stages of the osteoblast lineage. Here, primary human mandibular osteoblast cultures were grown in the presence of epidermal growth factor (EGF), giving a proliferative, less differentiated phenotype, or of vitamin D(3) and hydrocortisone (D+Hc), giving a more differentiated phenotype. These cultures were compared with those of cells prepared in the absence of EGF or D+Hc by fluorescence-activated cell sorter using a panel of monoclonal antibodies to specific integrin heterodimers. To provide in vivo correlation, the same panel of antibodies was used to stain fresh-frozen, undemineralised sections of human mandibular bone. Under baseline conditions the alpha(3), alpha(5), alpha(v), alpha(v)beta(3), beta(3) and beta(1) integrin subunits were expressed strongly by the cells, with low-level expression of the alpha(1), alpha(2) and alpha(4) subunits. In the presence of EGF there was increased alpha(2) expression. With D+Hc, alpha(3) and alpha(5) expression was elevated. Immunohistochemical analysis demonstrated alpha(2), alpha(3), alpha(5), alpha(v)beta(3), beta(1) and beta(3) subunits in cells of the osteoblast lineage; alpha(2) staining was restricted to cells close to the bone surface whilst alpha(v)beta(3) and beta(3) were most frequently localised in the osteocytes. The results provide evidence that cells at successive stages of the osteoblast lineage show different patterns of integrin expression. These integrins may be important in cell-matrix interactions leading to osteoblast differentiation.

Antibodies, Monoclonal↗
PubMed2003

The role of phospholipases A2 in the stimulation of neutrophil motility by cobra venoms.

Neutrophil (PMN) accumulation frequently occurs at the site of snakebite as part of the inflammatory response to envenoming. We demonstrate here that the venoms of the cobras, Naja naja and N. mossambica, and two purified venom phospholipase A(2)s (PLA(2)s) isolated from the latter venom, stimulate CD11b translocation from the PMN granule store to the plasma membrane and enhance neutrophil motility on collagen-coated surfaces. These effects were partially attenuated by the PLA(2) inhibitor, aristolochic acid, and almost completely abolished by the specific cytosolic PLA(2) inhibitor, methylarachidonylfluorophosphonate (MAFP). Annexin V and inhibitors of collagenase, cyclo-oxygenase and lipo-oxygenase, all inhibited PMN motility to a variable extent. FACS analysis and confocal microscopy showed that Annexin V interfered with binding and rapid endocytosis of the venom PLA(2). These results indicate that venom and venom PLA(2) preparations first caused a non-enzymatic stimulation of PMN leading to the activation of cytosolic PMN PLA(2) and production of arachidonate metabolites involved in stimulation of PMN degranulation and motility. The evidence suggests that venom PLA(2) then interacts with anionic phospholipids exposed on stimulated PMN, becomes endocytosed, and then contributes itself to the production of chemoattractants responsible for PMN accumulation at the site of the snakebite.

Animals↗
PubMed1996

Expression of integrin subunits in normal and malignant human salivary gland cell clones and its regulation by transforming growth factor-beta 1.

In this study, we have examined the expression of integrin subunits in normal and malignant human salivary gland cell clones as well as its regulation by transforming growth factor-beta 1 (TGF-beta 1). By the analysis using immunofluorescence staining, an SV40 immortalized normal human salivary gland duct cell clone (NS-SVDC) with no tumorigenic ability by s.c. implantation into nude mice was identified to express the integrin beta 1, alpha 2, alpha 3 and alpha 6 subunits on the cell surface, while the expression of these subunits, except for beta 1 subunit, was reduced or completely diminished in a neoplastic human salivary gland duct cell clone (HSGc) with tumorigenic but not metastatic potential in nude mice and metastatic cell clones derived after in vitro exposure of HSGc to N-methyl-N-nitrosourea. In addition, immunoblot analysis also exhibited the same results as those obtained with immunofluorescence staining. The alpha 1 subunit was not demonstrable in any of the cell clones by both techniques. TGF-beta 1 augmented the expression of the beta 1 subunit in NS-SV-DC, while HSGc and metastatic cell clones demonstrated no changes in the expression of the beta 1 subunit in response to TGF-beta 1. These findings, therefore, suggest that there is an inverse relationship between the malignancy and the expression mode of integrin subunits, especially alpha 2 subunit, in human salivary gland cell clones with varying degrees of malignant potential, and that TGF-beta 1 is a positive regulatory factor in the expression of the beta 1 subunit in normal but not malignant cell clones.

Animals↗
PubMed1998

Integrin-mediated adhesion and signalling in ovarian cancer cells.

The integrins are a family of cell surface receptors which mediate cellular adhesion and signalling events. Our goal was to evaluate integrin function and signalling pathways in ovarian cancer cells. Ovarian cancer cell lines, NIH:OVCAR-3 and NIH:OVCAR-5, exhibited distinct extracellular matrix (ECM) binding preferences which were mediated primarily through beta1 integrin interactions. Western blot analysis was used to identify changes in cellular phosphotyrosine, focal adhesion kinase (FAK) and mitogen activated protein (MAP) kinase. Tyrosine phosphorylation of integrin-associated phosphoproteins was not enhanced in either cell type in response to adhesion onto ECM components or receptor crosslinking. FAK expression was greater in NIH:OVCAR-5 cells while MAP kinase activity was higher in NIH:OVCAR-3 cells. The data suggest that these two ovarian cancer cell lines exhibit specific ECM binding preferences and distinct differences in phosphotyrosine, focal adhesion and MAP kinase expression profiles.

Antigens, CD↗
PubMed1997

The expression of VLA integrins in the human tonsilla palatina.

The integrin receptors are a family of transmembrane glycoproteins comprising non-covalent heterodimers. They interact with a wide variety of ligands including extracellular matrix glycoproteins, complement and other cell, while their intracellular domains interact with the cytoskeleton. They participate in cell-matrix and cell-cell adhesion in many physiologically important processes including embryological development, hemostasis, thrombosis, wound healing, immune and nonimmune defense mechanisms, and in oncogenic transformation. This investigation was focused on the histological distribution of the beta 1-integrins in the human tonsil using an indirect immunoperoxidase method. Present data suggest that lymphocyte and antigen presenting cells (FDCs, IDCs, and macrophages) interact with each other following adhesion to extracellular matrix proteins (e.g. fibronectin) through their integrin receptors in order to carry out special immunological functions. In addition, stromal elements and epithelial components were shown to express VLA integrins providing interactions for tissue organization and compartmentalization.

Antibodies, Monoclonal↗
PubMed1999

Low doses of ultraviolet A radiation stimulate adhesion of human dermal fibroblasts by integrins in a protein kinase C-dependent pathway.

In this work, we have studied the modulation of fibroblast-extracellular matrix interactions by physiological doses of ultraviolet A (UV-A) radiation using an adhesion assay on collagen. We have shown that low doses of UV-A (20 kJ/m2) stimulate fibroblast adhesion while higher doses (100 and 200 kJ/m2) inhibit it. By measurement of the thiobarbituric acid reactive substances (TBARS) and use of the chain-breaking antioxidant vitamin E, no role of lipid peroxidation can be detected in these effects. By incubating fibroblasts with a specific protein kinase C (PKC) inhibitor, GF109203X, we have demonstrated that the stimulation of the adhesion by low doses of UV-A involves, at least in part, a PKC-dependent mechanism. In addition, using function-blocking antibodies of alpha 1, alpha 2 or alpha 5 integrin chains involved in extracellular matrix anchorage, we have shown that they decrease the stimulation of adhesion following low doses of UV-A radiation, demonstrating the involvement of these three integrin chains in this UV-A effect. In parallel, 20 kJ/M2 of UV-A are found to rapidly stimulate membrane expression of alpha 1, alpha 2 and alpha 5 integrin chains. This work, which underlines the involvement of integrins in UV-A effects, contributes to the evaluation of the mechanisms by which cell-matrix interactions modulate cell behaviour.

Adolescent↗
PubMedDate not supplied

Mesothelium expression of integrins in vivo and in vitro.

OBJECTIVE: To characterize the expression of alpha subunits of integrin adhesion molecules in peritoneal tissue in vivo and in vitro. METHOD: Peritoneum from the anterior abdominal wall (n = 22) and the serosa of the posterior uterus (n = 11) was obtained from women of reproductive age without endometriosis who were undergoing surgery for benign conditions. Immunohistochemical studies were performed on serial sections of peritoneum from the anterior abdominal wall, the uterine serosa, mesothelial monolayer cultures, and peritoneum explants from the abdominal wall using monoclonal antibodies to alpha subunits of integrin adhesion molecules. Electron microscopy was performed to localize these adhesion molecules in the mesothelium. RESULTS: The mesothelial expression of alpha integrin subunits was identical in the anterior peritoneum and uterine serosa. In vivo the mesothelium strongly expressed alpha 2 and alpha 3 and variably expressed alpha 6. In the monolayer cultures there was moderate/strong staining for alpha 2, alpha 3, and alpha 5; there was minimal expression of alpha v. In the explants there was moderate/strong expression of alpha 2, alpha 3, alpha 5, and alpha v; alpha 6 was variably expressed. The ultrastructure of the mesothelium was unique in the anterior peritoneum, uterine serosa, and the monolayer cultures. The integrin subunits were distributed throughout the cytoplasm, were expressed in the plasma membrane, and were present on the surface (i.e., towards the peritoneal cavity) of the mesothelium. CONCLUSION: Integrins are expressed by the mesothelium of the peritoneum. The mesothelium expression of integrins in vivo differs from that of the mesothelium integrin expression in monolayer culture and explant culture.

Antigens, CD↗
PubMed1997

Importance of the tubulointerstitium in human glomerulonephritis. II. Distribution of integrin chains beta 1, alpha 1 to 6 and alpha V.

Accumulation of extracellular matrix is important in the progression of glomerulonephritis. Since adherent cell types utilize integrins to bind and organize extracellular matrix proteins, we have assessed expression of the beta 1 integrins in sequential sections from 85 human renal biopsies and 4 normal kidneys by immunohistochemical staining. Our results demonstrate strong correlations between expression of the alpha 5 chain within the interstitium, the alpha V chain on proximal and distal tubular epithelium and the presence of chronic histological damage. Moreover, staining for interstitial alpha 5 and proximal and distal tubular alpha V were also strongly associated with expression of certain adhesion molecules (ICAM-1, VCAM-1, E-selectin and L-selectin) and the presence of macrophages within the interstitium, which have been linked, in an earlier study, with the degree of chronic histological damage and disease progression. However, in contrast to our earlier study of adhesion molecules, there were also associations between expression of integrin chains within the glomerulus and tubulointerstitium. For example, there were strong positive associations between staining for alpha 5 on glomerular endothelium and its expression on extraglomerular vascular endothelium and between both mesangial alpha 1 and podocyte alpha 3 and tubular staining for the common beta 1 subunit. While the functional significance of these associations is obscure, they suggest some kind of communication between cells in different sites in the kidney. There were also positive associations between staining for different integrins within the glomerulus, notably mesangial cell staining for alpha 2, glomerular endothelial cells staining for alpha 5 and glomerular epithelial cell alpha 3. These results suggest that there is a coordinated upregulation of integrin expression both within the tubulointerstitium and the glomerulus and that at least some of these integrins (interstitial alpha 5 and distal tubular alpha V) are associated with the expression of other adhesion molecules, macrophage infiltration and the presence of markers of disease progression (interstitial fibrosis and tubular atrophy).

Antigens, CD↗