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PubMed2002

The influence of platelet glycoprotein polymorphisms on receptor function and risk for thrombosis.

With regard to hemostasis and thrombosis, collagens are among the most important physiologic components of the extracellular matrix in their role as platelet activators. Differences in the rate of platelet activation markedly influence normal hemostasis and the pathological outcome of thrombosis. Thus, collagen receptors, such as the integrin alpha2beta1 and indirectly, GPIb alpha, represent a relatively unexploited target of pharmacological control and are only recently becoming appreciated as potential factors in the generic risk for thrombosis. In general, the importance platelet glycoprotein polymorphisms as genetic risk factors for arterial thrombosis is a new area of human genomics that needs to be carefully addressed. Discrepancies in the degree to which they are reported to contribute to risk for clinical thrombosis will only be resolved once there is a universal standard for clinical study design. Most of the clinical studies differ by patient population size, ethnicity, bias in the selection of patients and controls, plurality in clinical endpoints and variation of environmental factors. Despite these differences, there is substantial evidence that the integrin beta3 PlA2 haplotype, the GPIb alpha Met145 haplotype, the GPIb alpha -5C haplotype and the integrin alpha2 haplotype 1 (807T) each contribute to the risk for and morbidity of thrombotic disease. There may remain dispute as to the extent of their contribution. However, well-designed, large, prospective, genetic and epidemiologic studies are needed to clarify the role of these and other platelet receptor polymorphisms. Most importantly, the cumulative effects of multiple platelet and plasma glycoproteins SNPs to thrombotic risk must be evaluated concurrently. Additional in vitro studies of the functional relevance underlying these polymorphisms are needed to provide a sound biological explanation for the results of clinical correlations. The opportunity now exists to make significant inroads into the development of strategies for the prevention of thrombotic disease.

Genetic Predisposition to Disease↗
PubMed1996

The A-domain of integrin alpha 2 binds specifically to a range of collagens but is not a general receptor for the collagenous motif.

Integrin alpha 2 beta 1 is a major cellular receptor for collagens, but the molecular basis of its function is unknown. The alpha 2 subunit contains a von Willebrand factor A-domain (I-domain) in its N-terminal region, and it has been demonstrated recently that this domain binds specifically to collagen I. This interaction requires divalent cations (e.g., Mg2+) and native collagen conformation, as does binding of the parent integrin to collagen. The alpha 2 A-domain therefore has a number of functional similarities to the parent integrin, alpha 2 beta 1. However, while sequence specificity has been demonstrated for the parent integrin, no such observations have been made for the A-domain. In particular, it is not known whether the A-domain is responsible for sequence-specific recognition of collagens or whether it binds to the genetic collagenous motif. To investigate the ligand specificity of the alpha 2 A-domain, its binding to a range of collagenous ligands has been studied, with cation dependence, collagen triple-helicity, and inhibition by function-blocking antibodies as criteria for specificity. Binding of the parent integrin was examined for comparison. The alpha 2 A-domain was found to bind specifically to collagens I, II, IV and XI. The complement component C1q has a collagenous domain but this was unable to support specific binding of alpha 2 A-domain or alpha 2 beta 1. Furthermore, synthetic triple-helical collagenous peptides failed to act as specific ligands. In conclusion, the alpha 2 A-domain binds specifically to a range of extracellular matrix collagens, but it is not a receptor for all collagenous triple helices. By inference, these findings indicate the existence of an integrin-specific sequence motif within collagenous ligands recognised by the alpha 2 A-domain.

Antigens, CD↗
PubMed1997

Expression of integrin subunits and CD44 isoforms in psoriatic skin and effects of topical calcitriol application.

Increasing evidence suggests involvement of integrins and CD44 isoforms in the pathogenesis of psoriasis, contributing to uncontrolled keratinocyte proliferation, neovascularization, and invasion of inflammatory cells. We have analyzed immunohistochemically in situ expression of integrins (CD29, CDw49b, CDw49c, CDw49e, CDw49f) and CD44 isoforms (CD44 standard, CD44 var/v6, CD44 v10) on frozen sections of normal and psoriatic skin (nonlesional skin, lesional skin before and along with topical calcitriol treatment). We did not observe visual changes of immunoreactivity in normal as compared to nonlesional psoriatic skin, while the staining pattern of CDw49c, CDw49f, and CD29 was severely altered in untreated lesional psoriatic skin. Most markedly, CDw49c, CDw49f, and CD29 were focally upregulated in suprapapillar epidermal compartments of lesional psoriatic skin, a staining pattern that is in accordance with the phenomenon that was described by Pinkus as "squirting papilla". Additionally, an increased proportion of inflammatory and endothelial cells revealed immunoreactivity for CD44(std.) in untreated lesional psoriatic as compared to nonlesional psoriatic or normal skin. After 8 weeks of topical calcitriol treatment (15 micrograms/g ointment), the staining pattern for CDw49c, CDw49f and CD29 was markedly changed in epidermis of lesional psoriatic skin, reverting to the staining pattern characteristic for the nonlesional psoriatic or normal human skin, although epidermal expression of CDw49f was still upregulated and CDw49e-, CDw49f-, CD29-, and CD44(std.)-immunoreactive inflammatory and endothelial cells were still to be found in the dermal compartment.

Administration, Topical↗
PubMed1994

Immunolocalization of alpha 2, alpha 5, and alpha 6 integrin subunits in salivary tissue and adenomas of the parotid gland.

The localization of the integrin subunits alpha 2, alpha 5, alpha 6 was studied immunohistochemically in samples of normal salivary gland and in a series of 8 pleomorphic adenomas, 5 Warthin's tumors, and 2 basal cell adenomas. In normal salivary tissue, acinar and ductal cells expressed alpha 2 and alpha 6 chains at the basal cell pole facing the basement membrane. alpha 2 also localized at sites of cell-cell contact. No staining of the epithelial component was seen with alpha 5. The polarized expression of alpha 2 and alpha 6 subunits was retained in salivary adenomas. These subunits were present at the basal cell pole of solid nests, tubules and ducts of pleomorphic adenomas, as well as of the basal layer of the epithelium of Warthin's tumor, and of the trabecular structures of basal cell adenomas. The alpha 5 subunit was consistently expressed only by cells embedded in the myxoid or chondroid matrix of pleomorphic adenomas. We conclude that the pattern of a integrin subunit expression in salivary adenomas may be related to the "epithelial" or "mesenchymal" phenotype of the neoplastic cells.

Adenolymphoma↗
PubMed2004

Expression patterns of integrins on pleomorphic adenoma and adenoid cystic carcinoma: study on specimens and in vitro investigation of the effects of extracellular matrix on the expression of these adhesion molecules.

BACKGROUND: Pleomorphic adenoma (PA) and adenoid cystic carcinoma (ACC) are neoplasms of distinct behaviour, showing similar origin, cell components and marked presence of extracellular matrix (ECM). Interactions between cells and ECM are important in the biology of tumours, being partially mediated by integrins. This study investigated these interactions on PA and ACC using paraffin-embedded tissue and an in vitro model of these conditions. METHODS: Expression of integrins in paraffin-embedded samples was assessed by immunohistochemistry. Cells from PA and ACC were characterized using immunofluorescence, and integrin patterns of expression were investigated on cells cultivated on different ECM proteins. RESULTS: Luminal cells of both PA and ACC were more intensely positive for integrins than myoepithelial cells. In vitro studies revealed that PA cells expressed more integrins than ACC cells regardless the ECM protein present. CONCLUSIONS: This study revealed particular patterns of integrin expression in both specimens and in vitro models of PA and ACC. This might prove useful for a better understanding of the biology of these lesions.

Actins↗
PubMed2000

Integrin expression in oral hairy leukoplakia and normal tongue epithelium.

OBJECTIVE: To describe the expression of integrins in the epithelium of oral hairy leukoplakia (HL) and compare to that of normal lateral tongue epithelium. MATERIALS AND METHODS: Immunohistochemistry to identify integrins (alpha 2, alpha 3, alpha 5, alpha 6, alpha v, beta 1) was performed, using a standard biotin-streptavidin-peroxidase technique on five clinically and histologically confirmed frozen biopsy specimens of HL and five normal lateral tongue control tissues. RESULTS: Expression of integrins alpha 2, alpha 3, alpha 6, alpha v, beta 1 was seen both in HL epithelium and in normal control tissue. alpha 5 expression was not seen in HL or in control tissue epithelium. alpha 2 and alpha 3 were expressed mainly in the basal and suprabasal layers; alpha 6 expression was most intense on the basal surface of the basal cells, alpha v was expressed in the basal and suprabasal layers with more expression seen in the higher differentiated cell layers than the other integrins. beta 1 expression was seen in the basal and suprabasal layers only. No apparent difference between HL and normal oral mucosa was noted in the staining pattern of the various integrins. CONCLUSION: Integrins alpha 2, alpha 3, alpha 6, alpha v, beta 1 are expressed in HL and the expression pattern is not different from that of normal oral mucosa. alpha 5 is not expressed in HL or in normal oral epithelium.

Antigens, CD↗
PubMed2002

VEGF-C mediates cyclic pressure-induced endothelial cell proliferation.

Mechanical forces modulate endothelial cell functions through several mechanisms including regulation of gene transcription. In the present study, gene transcription by human umbilical vein endothelial cells (HUVEC) either maintained under control pressure (that is, standard cell culture conditions equivalent to 0.15 mmHg sustained hydrostatic pressure) or exposed to 60/20 mmHg sinusoidal pressures at 1 Hz were compared using Affymetrix GeneChip microarrays to identify cellular/molecular mechanisms associated with endothelial cell responses to cyclic pressure. Cyclic pressure selectively affected transcription of 14 genes that included a set of mechanosensitive proteins involved in hemostasis (tissue plasminogen activator), cell adhesion (integrin-alpha2), and cell signaling (Rho B, cytosolic phospholipase A2), as well as a unique subset of cyclic pressure-sensitive genes such as vascular endothelial growth factor (VEGF)-C and transforming growth factor (TGF)-beta2. The present study also provided first evidence that VEGF-C, the most highly induced gene under 60/20 mmHg, mediated HUVEC proliferation in response to this cyclic pressure. Cyclic pressure is, therefore, a mechanical force that modulates endothelial cell functions (such as proliferation) by activating a specific transcriptional program.

Cell Division↗
PubMed1997

Expression of three cell adhesion molecules in bladder carcinomas: correlation with pathological features.

Recently, independent studies have shown that the expression of two integrin chains, beta 4 and alpha 2, plus the epithelial cadherin are related to tumour progression in human bladder carcinomas. For the first time, we compare the expression of these three cell adhesion molecules using immunohistochemical analysis of consecutive cryosections from a series of 50 bladder tumors. E-cadherin, beta 4, and alpha 2 were strongly expressed in normal urothelium. A majority of non-invasive bladder cancers stained positively for E-cadherin (62%), whereas only 29% expressed normal positivity for alpha 2, and only 35% for beta 4. However, most invasive tumours presented an aberrant expression of alpha 2 (81%), beta 4 (100%), and E-cadherin (75%). We studied the correlation of immunoreactivity with histological grade and stage. The alpha 2 pattern was not correlated with stage and grade. In contrast, loss of normal beta 4 expression was significantly related to increasing tumour grade and deep invasion with a higher correlation for grade. Finally, E-cadherin expression was highly correlated with stage, but not with grade. Thus our results indicate that, although many invasive bladder tumours presented a disorder in expression of the two integrins alpha 2 and beta 4, E-cadherin appeared to be a better market of invasiveness in bladder carcinomas.

Adult↗
PubMed2004

Invasive potential induced under long-term oxidative stress in mammary epithelial cells.

Although the causal relationship between chronic inflammation and carcinogenesis has long been discussed, the molecular basis of the relation is poorly understood. In the present study, we focused on reactive oxygen species (ROS) and their signals under inflammatory conditions leading to the carcinogenesis of epithelial cells and found that repeated treatment with a low dose of H(2)O(2) (0.2 mmol/L) for periods of 2 to 4 days caused a phenotypic conversion of mouse NMuMG mammary epithelial cells from epithelial to fibroblast-like as in malignant transformation. The phenotypic conversion included the dissolution of cell-cell contacts, redistribution of E-cadherin in the cytoplasm, and up-regulation of a set of integrin family members (integrin alpha2, alpha6, and beta3) and matrix metalloproteinases (MMPs; MMP-3, -10, and -13), as analyzed using Northern blot analysis and quantitative reverse transcription-PCR. Gelatin zymography indicated post-transcriptional activation of gelatinases, including MMP-2 and -9. In parallel, p38 mitogen-activated protein kinase and extracellular signal-regulated kinase 1/2 were activated, which contributed to the induction of MMP-13, and a glutathione S-transferase pull-down assay showed the activation of a small GTPase, Rac1. Surprisingly, the prolonged oxidative treatment was sufficient to induce all of the aforementioned events. Most importantly, depending on the MMP activities, the epithelial cells exposed to oxidative conditions eventually acquired invasiveness in a reconstituted model system with a Matrigel invasion chamber containing normal fibroblasts at the bottom, providing the first substantial evidence supporting the direct role of ROS signals in the malignant transformation of epithelial cells.

Animals↗
PubMed2006

Mesenchymal progenitor cells communicate via alpha and beta integrins with a three-dimensional collagen type I matrix.

BACKGROUND/AIMS: The aim of our study was to investigate interactions of mesenchymal progenitor cells (MPCs) with collagen matrices. METHODS: Human bone-marrow-derived MPCs were cultivated in collagen type I gels with and without inhibition of beta(1)-integrin by a specific antibody. Collagen gel contraction, cell morphology, expression of integrin subunits and several genes related to matrix synthesis and turnover as well as MPC differentiation were analyzed over 14 days. RESULTS: Human MPCs markedly contracted free-floating collagen gels. Contraction was nearly completely inhibited by blocking beta(1)-integrin. Cellular morphology was elongated in the absence and mostly round in the presence of the antibody. Expression of integrin alpha(1), alpha(2) and beta(1) subunits showed several changes partly dependent on beta(1)-integrin blocking. Expression of matrix metalloproteinase-1 was elevated irrespective of beta(1)-integrin blocking and tenascin-C was subsequently induced during gel contraction. Spontaneous induction of chondrogenic, osteogenic or adipogenic differentiation was observed neither in the presence nor in the absence of the beta(1)-integrin antibody. CONCLUSION: Our results indicate that the interaction of human MPCs with fibrillar collagen type I involves beta(1)- and alpha-integrin subunits and induces changes in gene expression related to extracellular matrix synthesis and turnover but not differentiation to the chondrogenic, osteogenic or adipogenic phenotype.

Antibodies, Monoclonal↗
PubMed2007

Clarithromycin suppresses invasiveness of human lung adenocarcinoma cells.

BACKGROUND: It has been speculated that clarithromycin (CAM), a 14-membered ring macrolide, possesses antitumor effects besides antimicrobial and anti-inflammatory effects. METHOD: We evaluated the effects of CAM on the growth and invasiveness of A549 lung adenocarcinoma cells. RESULTS: Although CAM did not affect the growth of A549 cells, the Matrigel invasion assay showed that the potential of invasion was diminished by CAM treatment. When analyzed by flow cytometry, CAM suppressed alpha(2)- and beta(1)-integrin expression. Furthermore, thymidine phosphorylase (TP) expression was diminished by CAM treatment in a dose-dependent manner. A specific TP inhibitor also suppressed beta(1)-integrin expression in flow cytometric analysis. CONCLUSIONS: These results suggest that CAM may suppress invasive activity of A549 cells in part by diminishing the expression of TP, alpha(2)- and beta(1)-integrin, which may be a downstream signal of the TP pathway, and that CAM could be useful in the treatment of lung adenocarcinoma.

Adenocarcinoma↗
PubMed2002

Increased platelet-collagen interaction associated with double homozygosity for receptor polymorphisms of platelet GPIa and GPIIIa.

OBJECTIVE: There is considerable controversy regarding the clinical role of the single-nucleotide polymorphisms (SNPs) of the platelet glycoprotein receptor GPIa C807T and the Pl(A1/A2) of GPIIIa as cardiovascular risk factors. We hypothesized that two combined SNPs in their homozygous prothrombotic forms could clarify their pathophysiological impact. METHODS AND RESULTS: We identified a family with a striking history of premature cardiovascular events and a high frequency of the prothrombotic form of the two SNPs. From this family, the platelets of a healthy, 27-year-old propositus with this double homozygosity were compared with three matched male neutral gene variant controls. The propositus had shortened PFA-100 closure times and an increased platelet aggregation response to collagen. Platelet deposition to collagen was augmented under the blood flow conditions of a high shear rate model (1600 s(-1)). Platelet adhesion on collagen monomers was induced in a static system, leading to the promotion of subsequent procoagulant activity. CONCLUSIONS: The combined homozygous prothrombotic SNPs of GPIa and GPIIIa are associated with an increased platelet-collagen interaction and procoagulant activity that can be readily demonstrated in several independent systems. Our patient may serve as a useful model for the functional consequences of two combined, potentially procoagulant, platelet SNPs.

Adult↗
PubMed2005

Adiponectin acts as an endogenous antithrombotic factor.

OBJECTIVE: Obesity is a common risk factor in insulin resistance and cardiovascular diseases. Although hypoadiponectinemia is associated with obesity-related metabolic and vascular diseases, the role of adiponectin in thrombosis remains elusive. METHODS AND RESULTS: We investigated platelet thrombus formation in adiponectin knockout (APN-KO) male mice (8 to 12 weeks old) fed on a normal diet. There was no significant difference in platelet counts or coagulation parameters between wild-type (WT) and APN-KO mice. However, APN-KO mice showed an accelerated thrombus formation on carotid arterial injury with a He-Ne laser (total thrombus volume: 13.36+/-4.25 x 10(7) arbitrary units for APN-KO and 6.74+/-2.87x10(7) arbitrary units for WT; n=10; P<0.01). Adenovirus-mediated supplementation of adiponectin attenuated the enhanced thrombus formation. In vitro thrombus formation on a type I collagen at a shear rate of 250 s(-1), as well as platelet aggregation induced by low concentrations of agonists, was enhanced in APN-KO mice, and recombinant adiponectin inhibited the enhanced platelet aggregation. In WT mice, adenovirus-mediated overexpression of adiponectin additionally attenuated thrombus formation. CONCLUSIONS: Adiponectin deficiency leads to enhanced thrombus formation and platelet aggregation. The present study reveals a new role of adiponectin as an endogenous antithrombotic factor.

Adenoviridae↗
PubMed1997

Polymorphisms of the human platelet antigens HPA-1, HPA-2, HPA-3, and HPA-5 on the platelet receptors for fibrinogen (GPIIb/IIIa), von Willebrand factor (GPIb/IX), and collagen (GPIa/IIa) are not correlated with an increased risk for stroke.

BACKGROUND AND PURPOSE: A recent study has described a high incidence of the human platelet antigen (HPA)-1b alloantigen in patients with myocardial infarction. We investigated the distribution of gene polymorphisms of platelet glycoproteins (GPs) in patients with cerebrovascular disease (CVD) and stroke. The polymorphic systems we have studied are HPA-1 and HPA-3 on the fibrinogen receptor (GPIIb/IIIa), HPA-2 on the von Willebrand factor receptor (GPIb/IX), and HPA-5 on one of the platelet collagen receptors (GPIa/IIa). METHODS: DNA was isolated from peripheral blood collected from 218 consecutive stroke patients, 165 neurological inpatients without signs of CVD, and 321 healthy blood donors. The genotypes of HPA-1, HPA-2, HPA-3, and HPA-5 were determined by sequence specific primer polymerase chain reactions. RESULTS: The calculated allele frequencies were as follows: for CVD patients, HPA-1a/b 0.81/0.19, HPA-2a/b 0.91/0.09, HPA-3a/b 0.61/0.39, and HPA-5a/b 0.92/0.08; for inpatient HPA-1a/b 0.83/0.17, HPA-2a/b 0.91/0.09, HPA-3a/b 0.62/0.3 and HPA-5a/b 0.93/0.07; and for blood donors, HPA-1a 0.85/0.15, HPA-2a/b 0.94/0.06, HPA-3a/b 0.60/0.40, and HPA 5a/b 0.92/0.08. There were no statistically significant difference for the analyzed HPA polymorphism frequencies either between the CVD patients and the non-CVD inpatients or the CVD patients and blood donors. However, the HPA-1b genotype was slightly more frequent in patients (CVD and non-CVD) than in the healthy blood donors. CONCLUSIONS: Our results indicate that the HPA-1, HPA-2, HPA-3, and HPA-5 polymorphisms are not associated with an increased risk for stroke.

Adolescent↗
PubMed2002

The influence of platelet collagen receptor polymorphisms in hemostasis and thrombotic disease.

Extracellular collagens modulate the rate of platelet activation and thereby markedly influence hemostasis and thrombosis. Platelet receptors for collagens, such as the integrin alpha(2)beta(1), platelet glycoprotein (GP) VI or, indirectly, the GPIb complex, are unexploited targets of pharmacological control, and polymorphisms of these receptors have recently become factored into the genetic risk for thrombosis. Seemingly contradictory findings already exist with regard to the contribution of GPIbalpha and integrin alpha(2) polymorphisms, but these discrepancies will be resolved once there is better standardization of clinical studies. There is already substantial evidence that GPIbalpha VNTR A or B alleles, the GPIbalpha-5C allele, and integrin alpha(2) allele 1 (T(807)) each contribute to increased risk for morbidity in thrombotic disease. However, larger, prospective genetic and epidemiological studies are needed to clarify the role of each of these polymorphisms, the contribution of other platelet receptor polymorphisms, and the synergistic effects of combinations of these factors. In addition, in vitro studies that establish the functional relevance of these polymorphisms will provide sound biological explanations for the results of clinical correlation studies.

Antigens, CD↗
PubMed1997

Truncation of the cytoplasmic domain of beta3 in a variant form of Glanzmann thrombasthenia abrogates signaling through the integrin alpha(IIb)beta3 complex.

Glanzmann thrombasthenia is an inherited bleeding disorder characterized by absence or dysfunction of the platelet integrin alpha(IIb)beta3. Patient RM is a thrombasthenic variant whose platelets fail to aggregate in response to physiological agonists, despite the fact that they express abundant levels of alpha(IIb)beta3 on their surface. Binding of soluble fibrinogen or fibrinogen mimetic antibodies to RM platelets did not occur, except in the presence of ligand-induced binding site (LIBS) antibodies that transformed the RM integrin complex into an active conformation from outside the cell. Sequence analysis of PCR-amplified genomic DNA and platelet mRNA revealed a C2268T nucleotide substitution in the gene encoding the integrin beta3 subunit that resulted in an Arg724Ter mutation, producing a truncated protein containing only the first eight of the 47 amino acids normally present in the cytoplasmic domain. Functional analysis of both RM platelets and CHO cells stably expressing this truncated integrin revealed that the alpha(IIb)beta3Arg724Ter complex is able to mediate binding to immobilized fibrinogen, though downstream events, including cytoskeletally-mediated cell spreading and tyrosine phosphorylation of focal adhesion kinase, pp125FAK, fail to occur. These studies establish the importance of the membrane-distal portion of the integrin beta3 cytoplasmic domain in bidirectional transmembrane signaling in human platelets, and the role of integrin signaling in maintaining normal hemostasis in vivo.

Amino Acid Sequence↗