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At least 487 records · Page 27Linked to original sources
PubMed2005

C1qTNF-related protein-1 (CTRP-1): a vascular wall protein that inhibits collagen-induced platelet aggregation by blocking VWF binding to collagen.

CTRP-1 is a novel member of the C1qTNF-related protein family containing family characteristic collagen and TNF-like domains and shows marked expression in vascular wall tissue. We observed that recombinant human CTRP-1 specifically bound to fibrillar collagen and blocked collagen-induced platelet aggregation. CTRP-1 completely or partially prevented VWF and GPVI-Fc4 binding to collagen, respectively. However, GPVI-Fc4 failed to compete for the binding of CTRP-1 to collagen. CTRP-1 had no effects on alpha(2)beta(1) integrin I-domain binding to collagen. Using whole human blood under flow at low and high shear rates, CTRP-1 prevented platelets from accumulating on a collagen-coated surface but had no effects on "platelet-rolling" on a surface coated with VWF. These data suggest that CTRP-1 prevents collagen-induced platelet aggregation by specific blockade of VWF binding to collagen. By using the Folts vascular injury model in nonhuman primates (Macaca fascicularis), we were able to demonstrate that CTRP-1 can prevent platelet thrombosis in vivo. This effect was achieved in the absence of changes in activated-clotting time (ACT) and template cut bleeding times, suggesting that CTRP-1 has promising antiplatelet thrombotic activity and most likely acts by pacifying the thrombogenic site of vascular injury.

Animals↗
PubMed1999

Surface expression of major membrane glycoproteins on resting and TRAP-activated neonatal platelets.

Platelets of full-term newborns and those of healthy adult donors were compared for constitutive expression of surface glycoproteins (GP) Ia-IIa, GP Ib, GP IIb-IIIa, and GP IV and for their activation responses to an agonist by detection of surface expression of activation markers P-selectin and CD63. Resting neonatal platelets showed significantly lower expression of GP Ia-IIa, GP Ib, and GP IIb-IIIa. In contrast, the expression of GP IV was significantly higher compared with platelets of adults. The expression of activation markers P-selectin and CD63 was assessed after in vitro activating of platelets with 0-15 microM human thrombin receptor-activating peptide. At low concentrations of thrombin receptor-activating peptide, the extent of surface expression of activation markers did not differ significantly between adult and neonatal platelets. However, after activation with 15 microM thrombin receptor-activating peptide, the extent of surface expression of P-selectin and CD63 was significantly lower in neonatal platelets. Because of ethical reasons, our study was conducted on neonates with a moderate neonatal hyperbilirubinemia. The remote possibility that hyperbilirubinemia could influence the expression of platelet surface receptors and the reactivity of neonatal platelet cannot be excluded. The role of higher expression of GP IV on neonatal platelets, also seen in certain hematologic malignancies in adults, remains to be elucidated. The lower expression of platelet adhesive receptors and the limited ability to up-regulate granular glycoproteins may play a role in the impairment of function of neonatal platelets.

Adult↗
PubMed2006

Differential expression of platelet glycoprotein Ia/IIa in Taiwan Chinese corresponds to glycoprotein ia gene polymorphisms.

Glycoprotein (GP) Ia/IIa plays a key role in platelet function by acting as a primary receptor for subendothelial collagen, thereby contributing to arterial thrombosis. In this study, we found that the expression level of platelet GPIa/IIa among Taiwan Chinese varies over sixfold and this difference relates either to the GPIa gene 807 C/T dimorphisms or the appearance of BglII restriction sequence within intron G. This is the first study to demonstrate the wide variation of platelet GPIa/IIa density in an Oriental population and its correlation to the GPIa gene polymorphisms. These results provide useful tools for predicting platelet GPIa/IIa density of Chinese.

Adult↗
PubMed2002

Bone morphogenetic proteins, extracellular matrix, and mitogen-activated protein kinase signaling pathways are required for osteoblast-specific gene expression and differentiation in MC3T3-E1 cells.

Osteoblasts secrete a complex extracellular matrix (ECM) containing collagenous and noncollagenous proteins, bone morphogenetic proteins (BMPs), and growth factors. Osteoblast-specific gene expression requires ascorbic acid (AA)-dependent assembly of a collagenous ECM. Matrix responsiveness requires an alpha2beta1 integrin-collagen interaction and mitogen-activated protein kinase (MAPK) activity, which phosphorylates and activates the osteoblast-specific transcription factor Cbfa1. This study examines interactions between this integrin/MAPK-mediated pathway and signals initiated by BMPs contained in the osteoblast matrix. MC3T3-E1 cells were shown to constitutively express BMP-2, BMP-4, and BMP-7. Noggin, a specific BMP inhibitor, reversibly blocked AA-induced gene expression, indicating that BMP production by MC3T3-E1 cells was necessary for differentiation. The ability of exogenously added BMP-2, BMP-4, or BMP-7 to stimulate osteocalcin (OCN) and bone sialoprotein (BSP) mRNAs or OCN promoter activity was synergistically increased in cells that were actively synthesizing an ECM (i.e., were grown in the presence of AA). A minimum of 4 days of ECM accumulation was required for this synergistic response to be observed. Neither BMP-7, AA, nor a combination of these two treatments had major effects on Cbfa1 messenger RNA (mRNA) or protein levels, as would be expected if regulation was mainly at the posttranscriptional level. U0126, a specific inhibitor of MAPK/extracellular signal-regulated kinase (MEK), blocked AA- or BMP-7/AA-dependent gene expression in a time- and dose-dependent manner that was closely correlated with inhibition of extracellular signal-regulated kinase (ERK) phosphorylation. This work establishes that autocrine BMP production as well as integrin-mediated cell-collagen interactions are both required for osteoblast differentiation, and both these pathways require MAP kinase activity.

3T3 Cells↗
PubMed2001

Common variations in platelet glycoproteins: pharmacogenomic implications.

Atherosclerosis and its complications are the result of complex interactions between the environment and genetic factors. Platelets play an important role in this disease process and antiplatelet agents are an essential part of its treatment. However, individual response to antiplatelet therapy is variable and agents that are safe and effective in one individual may be ineffective or harmful in another. It is likely that genetic factors are involved in this variance as platelet, and platelet-associated proteins are highly polymorphic. Up to 30% of natural variation in platelet reactivity is related to genetic inheritance. Rare inherited defects of platelet function due to the absence or reduced surface expression of platelet adhesion receptors have long been recognised. These cause minor bleeding defects and are usually clinically apparent. Antiplatelet agents should be avoided in these situations. The importance of the more common genetic variations or polymorphisms, which result in minor changes in the expressed protein and are often clinically silent, is unknown. Investigations are ongoing into the role of this variation in platelet physiology. A number of polymorphisms in platelet surface glycoproteins have received particular attention; the (A1/2) polymorphism resulting in conformational change at the amino terminus of the beta-3 chain of the platelet fibrinogen receptor glycoprotein (GP) IIb/IIIa and polymorphisms in the platelet collagen (GPIa/IIa and GPVI) and von Willebrand receptors (GPIb-IX). The (A2) allele has been associated with resistance to the antiplatelet agent aspirin and increased platelet responsiveness. The GPIa polymorphism has been associated with increased surface expression of GPIa and increased platelet adhesion to collagen. Recently, conflicting reports of the association of these polymorphisms with coronary artery disease (CAD) and its complications have been described. Mutations have also been identified in other platelet surface receptors including the recently identified G(i)-linked platelet adenosine diphosphate (ADP) receptor (P2Y(12)), targeted by the antiplatelet agents ticlopidine and clopidogrel. These discoveries have stimulated interest in the role of genetic factors in platelet physiology. In this article, the current knowledge of the influence of genetic make-up on antiplatelet therapy is discussed.

Animals↗
PubMed2003

Inhibition of platelet adhesion to collagen as a new target for antithrombotic drugs.

Platelet adhesion to a damaged blood vessel is the initial trigger for arterial hemostasis and thrombosis. Platelets adhere to the subendothelium through an interaction with von Willebrand factor (VWF), which forms a bridge between collagen within the damaged vessel wall and the platelet receptor glycoprotein Ib/V/IX (GPIb), an interaction especially important under high shear conditions[1]. This reversible adhesion allows platelets to roll over the damaged area, which is then followed by a firm adhesion mediated by the collagen receptors (alpha(2)beta(1), GPVI, ) in addition[2] resulting in platelet activation. This leads to the conformational activation of the platelet alpha(IIb)beta3 receptor, fibrinogen binding and finally to platelet aggregation. Over the past decades, modulation of platelet function has been a strategy for the control of cardiovascular disease. Lately, drugs have been developed that target the fibrinogen receptor alphaIIbbeta3 or the ADP receptor and many of these promising compounds have been tested in clinical trials. However the development of products that interfere with the first step of hemostasis, i.e. the platelet adhesion, has lagged behind. In this review we want to discuss (i) the in vivo studies that were performed with compounds that target proteins involved in different adhesion steps i.e. the VWF-GPIb-axis, the collagen-VWF axis and the collagen-collagen receptor axis and (ii) the possible advantages these putative new drugs could have over the current antiplatelet agents.

Animals↗
PubMed2006

Matrix metalloproteinase-1 produced by human CXCL12-stimulated natural killer cells.

Natural killer (NK) cells play a key role in inflammation and tumor regression through their ability to migrate into tissues. CXCL12 is a chemokine that promotes lymphocyte invasion and migration into tissues; however, the mechanism for this process remains incompletely understood. In this study, we show that CXCL12 significantly enhanced CD16(+)CD56(+) human peripheral NK-cell invasion into type I collagen by the catalytic activity of matrix metalloproteinase-1 (MMP-1). Confocal immunofluorescence and co-immunoprecipitation studies suggest that MMP-1 colocalized with alpha(2)beta(1) integrin on CXCL-12-stimulated NK-cell surface. The binding of pro-MMP-1 with alpha(2)beta(1) integrin required activation of G(i)-coupled pathway. However, the production of MMP-1 from CXCL12-stimulated NK cells was mediated by p38 and mitogen-activated or extracellular signal-regulation protein kinase kinase 1/2 in a manner independent of the G(i)-coupled pathway. These results suggest that CXCL12/CXCR4 interaction transduces the two signaling pathways to promote NK-cell invasion, which stimulates pericellular degradation of extracellular matrix proteins by membrane-associated MMP-1. The mechanisms would thus play a role in facilitating lymphocyte trafficking and accumulation in tissues during physiological and pathological processes.

CD56 Antigen↗
PubMed2003

Expression and functional importance of collagen-binding integrins, alpha 1 beta 1 and alpha 2 beta 1, on virus-activated T cells.

Adhesive interactions are crucial to cell migration into inflammatory sites. Using murine lymphocytic choriomeningitis virus as an Ag model system, we have investigated expression and function of collagen-binding integrins, alpha(1)beta(1) and alpha(2)beta(1), on activated and memory T cells. Using this system and MHC tetramers to define Ag-specific T cells, we demonstrate that contrary to being VLAs, expression of alpha(1)beta(1) and alpha(2)beta(1) can be rapidly induced on acutely activated T cells, that expression of alpha(1)beta(1) remains elevated on memory T cells, and that expression of alpha(1)beta(1) parallels that of viral-specific effector CD8(+) T cells (defined by tetramer and IFN-gamma staining). In an adoptive transfer model, mAb-mediated blockade of these integrins on activated effector and memory T cells inhibited Ag-specific delayed-type hypersensitivity responses; similar decreased responses were seen upon transfer of alpha(1)-deficient activated/memory T cells. Thus, expression of alpha(1)beta(1) and alpha(2)beta(1) integrins on activated T cells is directly functionally important for generation of inflammatory responses within tissues. Finally, the inhibitory effect of alpha(1)beta(1) blockade on the delayed-type hypersensitivity response could be bypassed by direct injection of Ag-specific T cells to inflammatory sites, demonstrating for the first time in vivo that collagen-binding integrins are involved in leukocyte migration into tissues.

Adoptive Transfer↗
PubMedDate not supplied

Effects of interferon-alpha on cellular proliferation and adhesion of breast carcinoma cells.

We examined the potent inhibitory effects of interferon-alpha (IFN-alpha) on both cellular adhesion and cell proliferation of MCF-7 breast carcinoma cells. When MCF-7 cells were exposed to IFN-alpha at a concentration of 5x10(3) IU/ml for 5 days, cell proliferation was markedly inhibited. Cell attachment assay demonstrated that incubation with IFN-alpha for up to 48 h reduced alpha2beta1 integrin-mediated cellular adhesion. However, fluorescence activated cell sorter (FACS) analysis revealed that incubation with IFN-alpha for 24 h had no effect upon the cell surface expressions of either alpha2 and beta1 integrin on MCF-7 cells. These antiproliferative and antiadhesive actions of IFN-alpha may be applied to treatment for patients with metastatic breast carcinoma.

Breast Neoplasms↗
PubMed2001

[Study of C807T polymorphism of the platelet collagen receptor alpha2 gene coding sequence in Suzhou Han population].

OBJECTIVE: To study the C807T polymorphism of the platelet collagen receptor alpha(2) gene coding sequence in Suzhou Han population. This polymorphism was associated with the expression density of integrin alpha(2)beta(1) on the platelet surface. METHODS: An amplified 1332 bp fragment of human alpha(2) gene from 110 unrelated individuals was analyzed by Bgl II and Ase I restriction assay. The resulting products were electrophoresed in 8% polyacrylamide gels and stained with ethidium bromide. RESULTS: The allelic frequencies were 0.291:0.709 for T807 allele: C807 allele in Suzhou Han population. The total theoretical heterozygous rate was 41%. The genotypic frequencies were 0.018:0.546:0.436 for homozygous 807T allele: heterozygous 807C/T allele: homozygous 807C allele. CONCLUSION: The C807T polymorphism of the platelet collagen receptor alpha2 gene in Suzhou Han population was different from that observed in other populations.

Asian People↗
PubMed2000

[Expression of type I collagen and its receptor system in osteoblasts].

OBJECTIVE: To study the expression of type I collagen and its receptor system-integrin alpha 2 beta 1 in different passages of osteoblasts. METHODS: The expression of type I collagen and integrin alpha 2 beta 1 in the primary, sixth and fifteenth passage of osteoblasts were detected by S-P immunohistological staining technique, and their mRNA expression by quantity RT-PCR technique. RESULTS: Type I collagen and integrin alpha 2 beta 1 were expressed in different passages of osteoblasts and there was no significant difference among three passages by immunohistological technique. Their mRNA expression was gradually decreased with subculture. CONCLUSION: Type I collagen promotes the adhesion and phenotype expression of osteoblasts through its receptor-integrin alpha 2 beta 1. The reductive expression of type I collagen-receptor system will decline the phenotype of osteoblasts.

Cells, Cultured↗
PubMed2002

Blockade of platelet GPIIB-IIIA (Integrin alphaII(b)beta(3)) in flowing human blood leads to passivation of prothrombotic surfaces.

We examined the impact of platelet activation on platelet adhesion to collagen in flowing human blood. ADP activation of platelets in ex vivo flowing blood resulted in paradoxical inhibition of platelet deposition on collagen. Blockade of fibrinogen binding to platelets by Lamifiban, a competitive antagonist of GPIIb-IIIa (integrin alpha(IIb)beta(3)), reversed this inhibition, leading to a marked increase in integrin alpha(2)beta(1)-dependent platelet adhesion. Analysis of integrin alpha(2)beta(1)-dependent platelet adhesion to collagen indicated that ADP-induced suppression of platelet adhesion is the result of trans-dominant inhibition of integrin alpha(2)beta(1) caused by fibrinogen binding to integrin GPIIb-IIIa. Lamifiban blocked fibrinogen binding, reversing the trans-dominant inhibition of alpha(2)beta(1) dependent adhesion to collagen. The GPIIb-IIIa antagonist resulted in the formation of a non-thrombogenic, passivated surface comprised of an adherent platelet monolayer. This unexpected consequence of blocking fibrinogen binding to GPIIb-IIIa may explain the long-term benefits of short-term GPIIb-IIIa antagonist treatment of Acute Coronary Syndrome patients.

Adenosine Diphosphate↗
PubMed2003

Diabetes duration may modify the association between genetic variation in the glycoprotein Ia subunit of the platelet collagen receptor and risk of severe diabetic retinopathy: a working hypothesis.

Genetic factors appear to contribute to the severity and progression of diabetic retinopathy. We assessed the associations of the C807T and Glu505Lys variants of the glycoprotein Ia (alpha(2) integrin) subunit of the platelet/endothelial collagen receptor and risk of retinopathy in a population-based survey of 288 diabetic patients in one Swedish community. Neither variant was associated with retinopathy risk overall. However, the 807T variant was associated with increased risk of severe retinopathy, and the association was modified by diabetes duration. Among patients with diabetes of longer duration (>/=25 years), the 807T variant was strongly associated with risk of severe retinopathy (odds ratio 7.49, 95% confidence interval 1.75 to 32.1). There was no association between the 807T variant and risk of severe retinopathy among patients with diabetes duration <25 years. The Lys505 variant of glycoprotein Ia was associated with an odds ratio for severe retinopathy of 1.88 (95% confidence interval 0.83 to 4.24). Overall, there was a significant interaction between glycoprotein Ia genotype and duration of diabetes on the risk of retinopathy (P-value for interaction = 0.019). These results suggest the hypothesis that genetic variation of platelet glycoprotein Ia may play a particularly important role during the advanced stages of diabetic retinopathy.

Adult↗
PubMed2000

[The modulation of type I collagen and its receptor system on biological characteristics of osteoblasts].

This paper addresses the question whether type I collagen-receptor system is necessary for the functional activity of osteoblasts. Through blocking type I collagen-receptor system by type I collagen antibody or integrin alpha 2 beta 1 antibody, the proliferation of osteoblasts was studied by cell count, the apoptosis was studied by flow cytometry, and the mRNA expressions of type I collagen, integrin alpha 2 beta 1 and osteocalcin were also detected by RT-PCR techniques. When type I collagen-receptor system was blocked, osteoblasts showed high apoptosis rate, lower growth kinetics and weak mRNA expression of type I collagen, integrin alpha 2 beta 1 and osteocalcin; the blocking effect was reversible. It suggests that type I collagen-receptor system is necessary for osteoblastic phenotype. The biomaterials for bone tissue engineering should be constructed according to the extracellular matrix of osteoblasts, which supply normal extracellular environment for osteoblasts.

Apoptosis↗
PubMed2003

[A preliminary study on the identification and distribution of epidermal stem cells in different degrees of burn wounds in scalded rats].

OBJECTIVE: To investigate the distribution of epidermal stem cells (ESCs) in different degrees of burn wounds in scalded rats. METHODS: Thirty-two Sprague-Dawley (SD) rats were employed in the study. First degree (I), shallow (shallow II) and deep partial thickness (deep II) and full thickness burn wounds (III) were created on the rat skin. Burn wound samples were harvested at 24 postburn hours (PBHs) from all the wounds and were processed to tissue slices. The tissue slices were stained by immunohistochemistry technique. The expression and distribution of ESCs in different degrees of burn wounds were observed with integrins alpha 2 beta 1 and keratin 10 (K10) as first antibodies. RESULTS: K10 positive cells were found to distribute in the strata spinosum, granulosum and lucidum in the first degree burn wound (I) with large amounts of integrins alpha 2 beta 1 positive cells in the residual basal layer and skin appendages (hair follicles) in shallow partial thickness burn wound (shallow II degree), and there were less integrins alpha 2 beta 1 positive cells in the remaining skin appendages in deep dermis in deep partial thickness burn wound (deep II degree). Finally, integrins alpha 2 beta 1 positive cells were sparsely found in the III degree burn wound. CONCLUSION: The distribution of ESCs in burn wounds was closely related to the depth of burn wound. The residual ESCs might be the origin of burn wound regeneration and reepithelization.

Animals↗
PubMed2005

[Effects of dermal template on the biological behaviors of fibroblasts during wound healing].

OBJECTIVE: To study the effects of dermal template on the biological behaviors of fibroblasts during wound healing. METHODS: A total of 120 rats were made full-thickness wound modes on the dorsum and divided into 4 groups, in group 1, the wounds were allowed to heal by contraction(ConT); in group 2, the wounds covered with full-thickness skin grafts (FTSG); in group 3, the wounds were with split thickness skin grafts (STSG); and in group 4, the wounds were covered by dermal regeneration template with overlying thin split-thickness autograft (ADMT). The specimens were obtained at one week, two weeks, four weeks, six weeks, and twelve weeks respectively. The expressions of alpha smooth muscle actin(alpha-SMA, characteristic of MFB), fibronectin (FN), integrin alpha2 beta1 and transforming growth factor beta1 (TGF-beta1) were examined by immunohistochemical analysis. RESULTS: Positive expression of alpha-SMA, FN, integrin alpha2 beta1 and TGF-beta1 in ADMT groups was significantly lower than that in STSG group and ConT group, but higher than that in FTSG group (P < 0.05). CONCLUSION: Dermal regeneration template can inhibit the transformation of FB to MFB and restrain the expression of FN, integrin alpha2 beta1, and TGF-beta1 in fibroblasts which might reduce the possibility of hypertrophic scarring, and improve wound healing.

Actins↗
PubMedDate not supplied

Genetic factors underlying differential blood platelet sensitivity to inhibitors.

Blood platelets are not only the primary defence mechanism involved in physiological hemostasis, but also their disorders constitute a crucial risk factor in arterial thrombosis. As arterial thrombi are composed of predominantly platelets formed under conditions of elevated shear stress at sites of atherosclerotic vascular injury and disturbed blood flow, the prevention of arterial thrombosis has been for years the main target for antiplatelet therapy. Individual differences in the rate of platelet activation and reactivity markedly influence normal hemostasis and the pathological outcome of thrombosis. Such an individual variability is largely determined by environmental and genetic factors. These are known to either hamper platelets' response to agonists, and thereby mimic the pharmacological modulation of platelet function or mask therapy effect and sensitize platelets. Some clinical studies have indicated that platelet glycoprotein polymorphisms are genetic factors contributing to arterial thrombosis. In spite of some discrepancies between different studies, there is substantial evidence that the integrin beta3 P1(A2) allele, the variants GPIbalpha Met145 and GPIbalpha (-5C) haplotype or the integrin alpha2 haplotype 1 (807T) each contribute to the risk for and morbidity of thrombotic disease. In this article, we reviewed a role of the aforementioned polymorphisms in modulating platelet function and platelet response to inhibitors. The paper focuses on the association between Pl(A1/A2) polymorphism and sensitivity (or resistance) to aspirin and the inhibitory efficacy of GPIIb-IIIa antagonists. Additionally, a potential role of 807C/T polymorphism (GPIa), polymorphisms of GPIb and platelet purinoreceptor P2Y12 in affecting platelet sensitivity to blocking agents is discussed.

Blood Platelets↗
PubMed2005

[Expression of platelet collagen receptor-glycoprotein VI fragment in E. coli and its biological activities].

This study was aimed to further investigate the function of platelet collagen receptor-glycoprotein VI and to screen its specific inhibitor. The extracellular domain of platelet glycoprotein VI (GPVI) in E. coli was expressed by recombinant technology, the extracellular domain cDNA of GPVI was amplified from pBluescript KS(-)-GPVI plasmid by PCR. Proved by sequencing, the expression vector pET-20b(+)-GPVI was constructed, which was then transformed into E. coli (BL21(DE3)pLysS) and induced by IPTG. The recombinant GPVI was purified on Ni-NTA resin column and renatured in PBS containing GSH and GSSG. The anti-penta His McAb and anti-GPVI polyclonal antibody were used to identify the recombinant GPVI in Western blotting. Collagen binding test was conducted to investigate the biological activity of recombinant GPVI. The results showed that the recombinant GPVI was expressed in E. coli and successfully purified, which was confirmed to be similar to the native GPVI in Western blotting. The recombinant GPVI can bind the type I collagen in dose-dependent manner. In conclusion, the recombinant GPVI can be achieved in E. coli and restore its native characteristics after renaturation.

Blood Platelets↗