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Measurement of the Interaction Between Recombinant I-domain from Integrin alpha 2 beta 1 and a Triple Helical Collagen Peptide with the GFOGER Binding Motif Using Molecular Force Spectroscopy  [PDF]
Simon J. Attwood,Anna M. C. Simpson,Samir W. Hamaia,Dominique Bihan,Debdulal Roy,Richard W. Farndale,Mark E. Welland
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms14022832
Abstract: The role of the collagen-platelet interaction is of crucial importance to the haemostatic response during both injury and pathogenesis of the blood vessel wall. Of particular interest is the high affinity interaction of the platelet transmembrane receptor, alpha 2 beta 1, responsible for firm attachment of platelets to collagen at and around injury sites. We employ single molecule force spectroscopy (SMFS) using the atomic force microscope (AFM) to study the interaction of the I-domain from integrin alpha 2 beta 1 with a synthetic collagen related triple-helical peptide containing the high-affinity integrin-binding GFOGER motif, and a control peptide lacking this sequence, referred to as GPP. By utilising synthetic peptides in this manner we are able to study at the molecular level subtleties that would otherwise be lost when considering cell-to-collagen matrix interactions using ensemble techniques. We demonstrate for the first time the complexity of this interaction as illustrated by the complex multi-peaked force spectra and confirm specificity using control blocking experiments. In addition we observe specific interaction of the GPP peptide sequence with the I-domain. We propose a model to explain these observations.
Conditional Knockout of Integrin α2β1 in Murine Megakaryocytes Leads to Reduced Mean Platelet Volume  [PDF]
David Habart, Yann Cheli, Diane J. Nugent, Zaverio M. Ruggeri, Thomas J. Kunicki
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0055094
Abstract: We have engineered a transgenic mouse on a C57BL/6 background that bears a floxed Itga2 gene. The crossing of this mouse strain to transgenic mice expressing Cre recombinase driven by the megakaryocyte (MK)-specific Pf4 promoter permits the conditional knockout of Itga2 in the MK/platelet lineage. Mice lacking MK α2β1 develop normally, are fertile, and like their systemic α2β1 knockout counterparts, exhibit defective adhesion to and aggregation induced by soluble type I collagen and a delayed onset to low dose fibrillar collagen-induced aggregation, results consistent with blockade or loss of platelet α2β1. At the same time, we observed a significant reduction in mean platelet volume, which is consistent with the reported role of α2β1 in MK maturation and proplatelet formation in vivo. This transgenic mouse strain bearing a floxed Itga2 gene will prove valuable to distinguish in vivo the temporal and spatial contributions of α2 integrin in selected cell types.
Non-Invasive Molecular Imaging of Fibrosis Using a Collagen-Targeted Peptidomimetic of the Platelet Collagen Receptor Glycoprotein VI  [PDF]
Julien Muzard, Laure Sarda-Mantel, Stéphane Loyau, Alain Meulemans, Liliane Louedec, Claudie Bantsimba-Malanda, Florence Hervatin, Jo?lle Marchal-Somme, Jean Baptiste Michel, Dominique Le Guludec, Philippe Billiald, Martine Jandrot-Perrus
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005585
Abstract: Background Fibrosis, which is characterized by the pathological accumulation of collagen, is recognized as an important feature of many chronic diseases, and as such, constitutes an enormous health burden. We need non-invasive specific methods for the early diagnosis and follow-up of fibrosis in various disorders. Collagen targeting molecules are therefore of interest for potential in vivo imaging of fibrosis. In this study, we developed a collagen-specific probe using a new approach that takes advantage of the inherent specificity of Glycoprotein VI (GPVI), the main platelet receptor for collagens I and III. Methodology/Principal Findings An anti-GPVI antibody that neutralizes collagen-binding was used to screen a bacterial random peptide library. A cyclic motif was identified, and the corresponding peptide (designated collagelin) was synthesized. Solid-phase binding assays and histochemical analysis showed that collagelin specifically bound to collagen (Kd 10?7 M) in vitro, and labelled collagen fibers ex vivo on sections of rat aorta and rat tail. Collagelin is therefore a new specific probe for collagen. The suitability of collagelin as an in vivo probe was tested in a rat model of healed myocardial infarctions (MI). Injecting Tc-99m-labelled collagelin and scintigraphic imaging showed that uptake of the probe occurred in the cardiac area of rats with MI, but not in controls. Post mortem autoradiography and histological analysis of heart sections showed that the labeled areas coincided with fibrosis. Scintigraphic molecular imaging with collagelin provides high resolution, and good contrast between the fibrotic scars and healthy tissues. The capacity of collagelin to image fibrosis in vivo was confirmed in a mouse model of lung fibrosis. Conclusion/Significance Collagelin is a new collagen-targeting agent which may be useful for non-invasive detection of fibrosis in a broad spectrum of diseases.
Absence of Platelet Phenotype in Mice Lacking the Motor Protein Myosin Va  [PDF]
Matthew T. Harper, Marion T. J. van den Bosch, Ingeborg Hers, Alastair W. Poole
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053239
Abstract: Background The motor protein myosin Va plays an important role in the trafficking of intracellular vesicles. Mutation of the Myo5a gene causes Griscelli syndrome type 1 in humans and the dilute phenotype in mice, which are both characterised by pigment dilution and neurological defects as a result of impaired vesicle transport in melanocytes and neuroendocrine cells. The role of myosin Va in platelets is currently unknown. Rab27 has been shown to be associated with myosin Va cargo vesicles and is known to be important in platelet dense granule biogenesis and secretion, a crucial event in thrombus formation. Therefore, we hypothesised that myosin Va may regulate granule secretion or formation in platelets. Methodology/Principal Findings Platelet function was studied in vitro using a novel Myo5a gene deletion mouse model. Myo5a?/? platelets were devoid of myosin Va, as determined by immunoblotting, and exhibited normal expression of surface markers. We assessed dense granule, α-granule and lysosomal secretion, integrin αIIbβ3 activation, Ca2+ signalling, and spreading on fibrinogen in response to collagen-related peptide or the PAR4 agonist, AYPGKF in washed mouse platelets lacking myosin Va or wild-type platelets. Surprisingly, Myo5a?/? platelets showed no significant functional defects in these responses, or in the numbers of dense and α-granules expressed. Conclusion Despite the importance of myosin Va in vesicle transport in other cells, our data demonstrate this motor protein has no non-redundant role in the secretion of dense and α-granules or other functional responses in platelets.
Effect of in vitro Glycation of Human Placental Collagen (Type IV) on Platelet Aggregation  [PDF]
Goodarzi Mohammad Taghi,Rezaei Mohsen,Piry Hossein,Amiry Saied
Pakistan Journal of Biological Sciences , 2005,
Abstract: The aim of this study was to analyze the in vitro glyation of human placental collagen (type IV) and to test the effect of glycation on its platelet aggregation activity. After isolation of collagen IV from a normal human placenta, it was glycated using different glucose concentration and different time of incubation. Glycation was measured using thiobarbituric acid colorimetric reaction. Using a turbidimetric method effect of glycated collagen on platelet aggregation was studied and compared with those of non-glycated collagen. The data obtained from this study indicated that collagen underwent in vitro glycation reaction and the level of glycation was dependent on glucose concentration and time of treatment with glucose (p<0.01). Glycated collagen increased platelet aggregation compared with native collagen (p<0.01). These results suggest that hyper-aggregability of platelet in interaction with glycated collagen can be the result of modification in collagen structure. The observed carbohydrate-induced modification apparently have a major impact on molecular conformation of the collagen IV, which might be the molecular basis for pathophysiological changes observed in diabetic microvascular complications.
Interaction between integrin αIIbβ3 and synthesized cyclic hexapeptide containing RGD
Bin Hu,Senfang Sui,Zeno Guttenberg,Michael Baermann,Erich Sackmann
Chinese Science Bulletin , 2000, DOI: 10.1007/BF02886319
Abstract: The RGD sequence generally exists in the extracellular matrix proteins and can be recognized by many integrin proteins. The binding ability of immobilized biotinylated cyclic hexapeptide [cyclo(-Arg-Gly-Asp-D-Phe-Lys-Gly-)] containing RGD to integrin ααbβ3 was tested by the methods of ELISA and SPR. Results showed that a spacer of 1.48–2.2 nm between the peptide and the biotin residue was long enough to send the RGD sequence into the binding center embccedded within αIIbβ3, and the equilibrium dissociation constant was 1.1 μm. The work provides an ideal model system for the research of cell adhesion on solid surfaces.
Pregnancy-Specific Glycoproteins Bind Integrin αIIbβ3 and Inhibit the Platelet—Fibrinogen Interaction  [PDF]
Daniel K. Shanley, Patrick A. Kiely, Kalyan Golla, Seamus Allen, Kenneth Martin, Ronan T. O’Riordan, Melanie Ball, John D. Aplin, Bernhard B. Singer, Noel Caplice, Niamh Moran, Tom Moore
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0057491
Abstract: Pregnancy-specific glycoproteins (PSGs) are immunoglobulin superfamily members encoded by multigene families in rodents and primates. In human pregnancy, PSGs are secreted by the syncytiotrophoblast, a fetal tissue, and reach a concentration of up to 400 ug/ml in the maternal bloodstream at term. Human and mouse PSGs induce release of anti-inflammatory cytokines such as IL-10 and TGFβ1 from monocytes, macrophages, and other cell types, suggesting an immunoregulatory function. RGD tri-peptide motifs in the majority of human PSGs suggest that they may function like snake venom disintegrins, which bind integrins and inhibit interactions with ligands. We noted that human PSG1 has a KGD, rather than an RGD motif. The presence of a KGD in barbourin, a platelet integrin αIIbβ3 antagonist found in snake venom, suggested that PSG1 may be a selective αIIbβ3 ligand. Here we show that human PSG1 binds αIIbβ3 and inhibits the platelet – fibrinogen interaction. Unexpectedly, however, the KGD is not critical as multiple PSG1 domains independently bind and inhibit αIIbβ3 function. Human PSG9 and mouse Psg23 are also inhibitory suggesting conservation of this function across primate and rodent PSG families. Our results suggest that in species with haemochorial placentation, in which maternal blood is in direct contact with fetal trophoblast, the high expression level of PSGs reflects a requirement to antagonise abundant (3 mg/ml) fibrinogen in the maternal circulation, which may be necessary to prevent platelet aggregation and thrombosis in the prothrombotic maternal environment of pregnancy.
Piezoresistance in chemically synthesized polypyrrole thin films  [PDF]
S. Barnoss,H. Shanak,C. Bof Bufon,T. Heinzel
Physics , 2009,
Abstract: The resistance of chemically synthesized polypyrrole (PPy) thin films is investigated as a function of the pressure of various gases as well as of the film thickness. A physical, piezoresistive response is found to coexist with a chemical response if the gas is chemically active, like, e.g., oxygen. The piezoresistance is studied separately by exposing the films to the chemically inert gases such as nitrogen and argon. We observe that the character of the piezoresistive response is a function not only of the film thickness, but also of the pressure. Films of a thickness below 70 nm show a decreasing resistance as pressure is applied, while for thicker films, the piezoresistance is positive. Moreover, in some films of thickness of about 70 nm, the piezoresistive response changes from negative to positive as the gas pressure is increased above 500 mbars. This behavior is interpreted in terms of a total piezoresistance which is composed of a surface and a bulk component, each of which contributes in a characteristic way. These results suggest that in polypyrrole, chemical sensing and piezoresistivity can coexist, which needs to be kept in mind when interpreting resistive responses of such sensors.
Transport properties of chemically synthesized polypyrrole thin films  [PDF]
C. C. Bof Bufon,T. Heinzel
Physics , 2007, DOI: 10.1103/PhysRevB.76.245206
Abstract: The electronic transport in polypyrrole thin films synthesized chemically from the vapor phase is studied as a function of temperature as well as of electric and magnetic fields. We find distinct differences in comparison to the behavior of both polypyrrole films prepared by electrochemical growth as well as of the bulk films obtained from conventional chemical synthesis. For small electric fields F, a transition from Efros-Shklovskii variable range hopping to Arrhenius activated transport is observed at 30 K. High electric fields induce short range hopping. The characteristic hopping distance is found to be proportional to F^(-1/2). The magnetoresistance R(B) is independent of F below a critical magnetic field, above which F counteracts the magnetic field induced localization.
Use of Platelet-Rich Plasma for Collagen Matrixes Revitalization with Human Fibroblast  [PDF]
Maxim Sergeevich Makarov, Natalya Valerjevna Borovkova, Olga Ivanovna Konushko, Valery Borisovich Khvatov
Journal of Biosciences and Medicines (JBM) , 2015, DOI: 10.4236/jbm.2015.310011
Abstract: We studied in vitro attachment, proliferation and survival of сadaver skin fibroblasts in collagen bands, dermal matrix and cancellous demineralized bone, enriched with platelet components. It was shown, that PRP enhanced revitalization of collagen grafts, especially followed by components of activated or freezed platelets. Fibroblasts had the best rate of proliferative activity in response to 150 pg platelet derived growth factor (PDGF), released from 100 million platelets with granules and measured for 100 × 103 cultivated cells. The use of platelet-derived material could increase fibroblast proliferation activity for 1.5-3 times in all types of collagen transplants without damage or decay of cell’s biological value.
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