bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sprouty proteins: antagonists of endothelial cell signaling and more
Authors: Cabrita Miguel , Christofori Gerhard 
Published: September 2003

SummaryAmong many signaling pathways, receptor tyrosine kinases (RTKs) can activate the mitogen-activated protein kinase (MAPK) signaling pathway that subsequently leads to a variety of cellular changes, including proliferation, differentiation and motility. The regulation of growth factor signaling is complex, and various cell types respond differently to the same stimulus for reasons not entirely understood. The recent discovery in Drosophila of Sprouty (dSpry), an inhibitor of RTK-induced MAPK activation, provides clues to how these signals are regulated. In mammals, four orthologues of dSpry, Spry1-4, have been described, and in this review we discuss their functional characteristics. Mammalian Sprys, like dSpry, are ligand-induced feedback inhibitors of a number of growth factor receptors. In endothelial cells, upon fibroblast growth factor (FGF) receptor and vascular endothelial growth factor (VEGF) receptor activation, Sprys translocate to the plasma membrane and inhibit cell growth and proliferation. However, in epidermal growth factor (EGF)-stimulated cells, Sprys can enhance MAPK activation. In addition, Sprys have many binding partners, including different effectors of the MAPK activation pathway. The intersection point where Sprys interfere in the MAPK pathway as well as their interactions with other proteins may partly explain the dual, yet opposing roles, on growth factor-induced MAPK activation. Moreover, Sprys require tyrosine phosphorylation to interact with their binding partners, a prerequisite for their dual function. Hence, Sprys add another layer of complexity to the regulation of RTK-mediated signal transduction that begins to explain the variation in cellular responses to growth factors.This publication was partially financed by Serono Foundation for the Advancement of Medical Science.Part of this paper was originally presented at the 2nd International Workshop on New Therapeutic Targets in Vascular Biology from February 6-9, 2003 in Geneva, Switzerland.
AMP-activated protein kinase (AMPK) regulates the insulin-induced activation of the nitric oxide synthase in human platelets
Authors: Schulz Christian , Fichtlscherer Birgit , Kemp Bruce , Fisslthaler Beate , Busse Rudi , Fleming Ingrid 
Published: September 2003

SummaryLittle is known about the signaling cascades that eventually regulate the activity of the endothelial nitric oxide synthase (eNOS) in platelets. Here, we investigated the effects of insulin on the phosphorylation and activation of eNOS in washed human platelets and in endothelial cells.Insulin activated the protein kinase Akt in cultured endothelial cells and increased the phosphorylation of eNOS on Ser1177but failed to increase endothelial cyclic GMP levels or to elicit the relaxation of endothelium-intact porcine coronary arteries. In platelets, insulin also elicited the activation of Akt as well as the phosphorylation of eNOS and initiated NO production which was associated with increased cyclic GMP levels and the inhibition of thrombin-induced aggregation. The insulin-induced inhibition of aggregation was accompanied by a decreased Ca2+response to thrombin and was also prevented by Nωnitro-L- arginine. In platelets, but not in endothelial cells, insulin induced the activation of the AMP-activated protein kinase (AMPK), a metabolic stress-sensing kinase which was sensitive to the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin and the AMPK inhibitor iodotubercidin. Moreover, the insulin-mediated inhibition of thrombin-induced aggregation was prevented by iodotubercidin. Insulin-independent activation of the AMPK using 5-aminoimidazole-4-carboxamide ribonucleoside, increased platelet eNOS phosphorylation, increased cyclic GMP levels and attenuated platelet aggregation.These results highlight the differences in the signal transduction cascade activated by insulin in endothelial cells and platelets, and demonstrate that insulin stimulates the formation of NO in human platelets, in the absence of an increase in Ca2+, by activating PI3-K and AMPK which phosphorylates eNOS on Ser1177.
Regulation of protease-activated receptor 1 (PAR1) on platelets and responsiveness to thrombin receptor activating peptide (TRAP) during systemic inflammation in humans
Authors: Reiter Rosemarie , Derhaschnig Ulla , Spiel Alexander , Keen Priska , Cardona Francesco , Mayr Florian , Jilma Bernd 
Published: September 2003

SummaryThrombin is a coagulation protease that activates platelets, endothelial cells, leukocytes and mesenchymal cells. Thrombin signaling is mediated at least in part by protease-activated receptors (PARs). As little is known about the in vivoregulation of PAR1, this study aimed to characterize the effects of systemic thrombin formation during human endotoxemia on the regulation of PAR1 and the associated responsiveness of human platelets to thrombin receptor activating peptide (TRAP). Endotoxin (2 ng/kg) was infused into 40 healthy men to study the regulation of PAR1 in systemic human inflammation. The SPAN12 antibody was used to determine the in vivoregulation of PAR1. To measure whether modulation of the PAR1 receptor may be associated with altered platelet reactivity, whole blood was stimulated with TRAP ex vivo. Thrombin generation was determined by prothrombin (F1+2) fragment. F1+2levels increased almost 9-fold from 0.5±0.1 nmol/L to 4.5±1.9 nmol/L at 4 h (p<0.001). PAR1 decreased by ~8% (p<0.001) within 2 h after endotoxin infusion and stayed at those levels until 6 h. Concomitantly, TRAP induced P-selectin expression maximally decreased by 18% (p<0.001) at 6 h. In conclusion, PAR1 expression is down-regulated on platelets during systemic thrombin formation induced by inflammation in humans which results in decreased responsiveness to subsequent stimulation of the PAR1 receptor.
Circulating endothelial cells in pulmonary hypertension
Authors: Golpon Heiko , Hebbel Robert , Solovey Anna , Cool Carlyne , Tuder Rubin , Geraci Mark , Voelkel Norbert , Bull Todd 
Published: September 2003

SummaryThe pulmonary endothelium plays a significant role in the pathobiology of Primary Pulmonary Hypertension. A number of diseases, related by a history of vascular injury, are associated with increased numbers of circulating endothelial cells (CECs). We hypothesized that patients with pulmonary hypertension would also have an increased number of circulating endothelial cells due to the high pressures and increased shear stress present within the pulmonary vasculature. We isolated the CECs from 14 patients with pulmonary hypertension, (5 primary and 11 secondary) and compared them to the cells from 12 normal controls. There was a significant increase in the number of CECs in peripheral blood in patients with both PPH and secondary pulmonary hypertension (SPH) when compared to normal volunteers (33.1 +/- 1.9 {PPH} and 27.2 +/- 6.9 {SPH} vs. 3.5 +/- 1.3 {controls}, p < 0.001). The number of circulating endothelial cells in the patient’s peripheral blood correlated significantly with the systolic, diastolic and mean pulmonary artery pressures of the individual. Approximately 50% of the CECs from patients with pulmonary hypertension expressed CD36, a marker of microvascular origin and 25% expressed E-selectin, a marker of endothelial cell activation. Although the origin of the CECs in patients with PH requires further investigation, one possible source is the pulmonary vasculature, and in patients with plexogenic pulmonary hypertension, the plexiform lesions. CECs may provide a non-invasive mean of accessing cells important to the pathobiology of severe pulmonary hypertension.
Plasmin generation dependent on α-enolase-type plasminogen receptor is required for myogenesis
Authors: López-Alemany Roser , Suelves Mònica , Muñoz-Cánoves Pura 
Published: September 2003

SummaryPlasmin is a potent extracellular protease specialized in the degradation of fibrin (fibrinolysis). Active plasmin is generated by proteolytic activation of the zymogen plasminogen (Plg) by urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). α-Enolase constitutes a receptor for plasminogen on several leukocyte cell types, serving to localize and promote plasminogen activation pericellularly. However, a role for α-enolase-type plasminogen receptor (PlgR) in myogenesis has never been demonstrated. In this study, we show that C2C12 mouse myoblasts express PlgR, being its expression greatly induced during the differentiation process. A monoclonal antibody against PIgR MAb 11G1, with cell surface-generated plasmin inhibitory abilities, was able to fully abrogate C2C12 myoblast fusion and differentiation in vitro. Moreover, both plasmin activity and PlgR expression were significantly induced in regenerating skeletal muscle in vivo, either in experimentally-injured muscle or in the dystrophic muscle of mdx mouse (an animal model of human Duchenne muscular dystrophy, DMD). The mdx muscle presents better regeneration capacities and less fibrosis than the human DMD muscle; therefore, the increase in PlgR/plasmin activity in mdx muscle suggests an important contribution of the fibrinolytic system in mdx regeneration. This study constitutes the first indication of α-enolase-type plasminogen receptor as an important component of skeletal myogenesis, by concentrating and enhancing plasmin generation on the cell surface.
Membrane-associated CD40L and sCD40L in atherothrombotic disease
Authors: X.Anand Sunil , Viles-Gonzalez Juan , Badimon Juan , Cavusoglu Erdal , Marmur Jonathan 
Published: September 2003

SummaryRecent data suggests that CD40L is involved in the pathogenesis of atherothrombotic disease. This review will focus on the history of CD40L, its role in platelet-mediated pathogenesis of atherothrombotic disease, its association to clinical syndromes and procedures, and its role in determining plaque rupture.
Stejnulxin, a novel snake C-type lectin-like protein from Trimeresurus stejnegeri venom is a potent platelet agonist acting specifically via GPVI
Authors: Lee Wen-Hui , Du Xiao-Yan , Lu Qiu-Min , Clemetson Kenneth , Zhang Yun 
Published: September 2003

SummaryStejnulxin, a novel snake C-type lectin-like protein with potent platelet activating activity, was purified and characterized from Trimeresurus stejnegeri venom. Under non-reducing conditions, it migrated on a SDS-polyacrylamide gel with an apparent molecular mass of 120 kDa. On reduction, it separated into three polypeptide subunits with apparent molecular masses of 16 kDa (α), 20 kDa (β1) and 22 kDa (β2), respectively. The complete amino acid sequences of its subunits were deduced from cloned cDNAs. The N-terminal sequencing and cDNA cloning indicated that β1 and β2 subunits of stejnulxin have identical amino acid sequences and each contains two N-glycosylation sites. Accordingly, the molecular mass difference between β1 and β2 is caused by glycosylation heterogenity. The subunit amino acid sequences of stejnulxin are similar to those of convulxin, with sequence identities of 52.6% and 66.4% for the α and β, respectively. Stejnulxin induced human platelet aggregation in a dose-dependent manner. Antibodies against αIIbβ3 inhibited the aggregation response to stejnulxin, indicating that activation of αIIbβ3 and binding of fibrinogen are involved in stejnulxin-induced platelet aggregation. Antibodies against GPIbα or α2β1 as well as echicetin or rhodocetin had no significant effect on stejnulxin-induced platelet aggregation. However, platelet activation induced by stejnulxin was blocked by anti-GPVI antibodies. In addition, stejnulxin induced a tyrosine phosphorylation profile in platelets that resembled that produced by convulxin. Biotinylated stejnulxin bound specifically to platelet membrane GPVI.
Risk factors for venous thrombosis in the black population
Authors: Patel Raj , Ford Elizabeth , Thumpston Jill , Arya Roopen 
Published: September 2003

SummaryRisk factors for venous thrombo-embolism (VTE) in the black population are poorly characterized. Of 142 black cases tested a genetic cause was identified in only 9.1%: 4.2% had protein C deficiency, 2.8% protein S deficiency, 0.7% antithrombin deficiency and 1.4% were heterozygous for FV Leiden. We hypothesised that elevated factor VIII levels constitute a candidate risk factor for venous thrombosis in the black population. Factor VIII (FVIII:C) levels were determined in 100 black patients with VTE and 100 black controls in a case-control study. Of the patients 34% had a FVIII:C above 228 IU/dL (the 90thcentile value in normal blacks) compared to 10% controls. Relative to those with FVIII:C below this value, odds ratio (OR) for risk of VTE was 4.64 (95% CI 2.02-10.85). When FVIII:C below 150 IU/dL was used as a comparator, OR was 11.1 (95% CI 4.29-29.43). There was evidence for a dose-response relationship. We propose that raised FVIII:C is a major risk factor for VTE in black subjects with prevalence and odds ratio exceeding those reported for white subjects.
Role of blood coagulation factor XIII in patients with acute pulmonary embolism. Correlation of factor XIII antigen levels with pulmonary occlusion rate, fibrinogen, D-dimer, and clot firmness
Authors: Kucher Nils , Schroeder Verena , Kohler Hans 
Published: September 2003

SummaryIn patients with acute pulmonary embolism (PE), pulmonary occlusion rate is directly related to D-dimer and inversely related to fibrinogen levels. The role of coagulation factor XIII (FXIII) levels in acute venous thromboembolism is not known. A total of 120 consecutive patients with suspected PE and VIDAS D-dimer levels >500 μg/L were investigated by helical computed tomography (CT). Pulmonary occlusion rate was assessed by CT using the modified Miller index. D-dimer, fibrinogen, and FXIII A- and B-subunit antigen levels were taken on admission. Thrombelastography (TEG) was performed in a subset of patients (n=12).The 71 patients with PE had lower FXIII A-subunit levels than the 49 patients with excluded PE (78.6±24.5% vs. 91.3±28.8%, p=0.01). In both groups, FXIII A-subunit was inversely related to D-dimer levels. FXIII A-subunit correlated with fibrinogen levels in patients with PE but not in patients without PE. FXIII A-subunit decreased with increasing pulmonary occlusion rate. The risk of PE was increased in the presence of A-subunit levels < 60% (OR 7.0 [95% CI 1.4-35.3], p=0.019). Clot firmness determined by TEG was lower in patients with PE than in patients without PE.In patients with PE, circulating FXIII A-subunit is decreased compared to patients with suspected but excluded PE. The higher the clot burden within the pulmonary arteries the lower the FXIII antigen. In these patients, direct relation of FXIII A-subunit to fibrinogen levels argues for significant consumption of these coagulation factors in PE. This consumption of FXIII can also be detected by a global coagulation test like TEG.
Increased plasma levels of plasminogen activator inhibitor-1 and soluble vascular cell adhesion molecule after triacylglycerol infusion in man
Authors: Krebs Michael , Geiger Margarethe , Polak Kaija , Vales Anja , Schmetterer Leopold , Wagner Oswald , Waldhäusl Werner , Roden Michael , Binder Bernd 
Published: September 2003

SummaryIncreased plasma plasminogen activator inhibitor-1 (PAI-1) has been implicated in the development of vascular disease. In type 2 diabetes mellitus high PAI-1 levels are associated with increased plasma concentrations of free fatty acids (FFA) and triacylglycerol indicating an association or a causal relationship. To answer that question, the effect of FFA/triacylglycerol on plasma PAI-1 was examined. Ten healthy male volunteers were studied for 6 h during infusion of triacylglycerol [1.5 ml/min]/heparin [0.2 IU/(kg·min)] (LIP; n=10), saline only (SAL; n=10), and saline/heparin (HEP; n=5). Plasma insulin concentrations were kept constant at ~35 pmol/l by intravenous soma-tostatin-insulin infusions and there was no significant change in plasma glucose levels during any of the study protocols. LIP increased plasma triacylglycerol and FFA ~3- (p<0.001) and ~8-(p<0.000001) fold, respectively, within 90 min. Baseline plasma PAI-1 measured by a bio-immunoassay was similar in HEP (11.4±2.8 ng/ml), SAL (16.6±3.6 ng/ml), and LIP studies (15.2±3.4 ng/ml). Since studies were initiated in the morning, PAI-1 decreased (p<0.025) over time following its normal diurnal variation to 6.4±2.0 ng/ml and 4.0±2.4 ng/ml at 360 min in SAL and HEP, respectively. During LIP, however, PAI-1 increased to ~2.6 fold higher levels than during SAL at 360 min (16.4±4.0 ng/ml, p<0.01). While tissue plasminogen activator (tPA) and adipsin, an adipocyte derived protease, were unaffected by LIP, changes in soluble vascular cell adhesion molecule-1 (sVCAM-1) were significantly correlated (p=0.02) with those seen for PAI-1. This suggests that hyperlipidemia independent of insulin and plasma glucose levels stimulates vascular tissue and in turn might induce an increase in plasma PAI-1. PAI-1 then could contribute to the development of atherothrombotic vascular disease.
Mechanisms of Leukotriene B4–Triggered Monocyte Adhesion
Authors: Friedrich Erik B. , Tager Andrew M. , Liu Emerson , Pettersson Annika , Owman Christer , Munn Lance , Luster Andrew D. , Gerszten Robert E. 
Published: September 2003

Objective—Leukotriene B4(LTB4) has been implicated in the trafficking of monocytes to inflammatory pathologic conditions, such as transplant rejection and atherosclerosis. The aim of this study was to determine the mechanisms by which LTB4contributes to monocyte capture from the circulation.Methods and Results—In in vitro and in vivo vascular models, the lipid chemoattractant LTB4was an equipotent agonist of monocyte adhesion compared with the chemokine monocyte chemoattractant protein-1 (MCP-1). Adenoviral gene transfer of specific endothelial adhesion molecules and blocking monoclonal antibody studies demonstrated that LTB4triggers both β1- and β2-integrin–dependent adhesion. Flow cytometry studies suggested that changes in integrin avidity or affinity, rather than alterations of integrin surface expression, were responsible for the chemoattractant-triggered arrest. Surprisingly, in contrast to the peptide chemokine MCP-1, LTB4did not activate the phosphoinositide 3-kinase pathway, which is a functionally critical step in chemokine-triggered effector functions.Conclusions—LTB4is a potent trigger of monocyte adhesion under flow yet mediates its effects via pathways that appear to differ from peptide chemoattractants. A better understanding of the mechanisms of LTB4-induced monocyte trafficking might shed insight into disease pathogenesis and pinpoint critical steps for therapeutic intervention for multiple human inflammatory pathologic conditions.
Meta-Analysis of 4 Coronary Heart Disease Genome-Wide Linkage Studies Confirms a Susceptibility Locus on Chromosome 3q
Authors: Chiodini Benedetta D. , Lewis Cathryn M. 
Published: September 2003

Objective—In coronary heart disease (CHD), 4 independent, genome-wide screens have now been published on Finnish, Mauritian, European, and Australian families. Results from these studies are inconclusive. We performed a meta-analysis to identify genetic regions that show evidence for susceptibility genes across studies.Methods and Results—The rank-based genome-scan meta-analysis (GSMA) method was applied to the 4 CHD genome-wide linkage studies. The strongest evidence for linkage was found on chromosomes 3q26–27 (P=0.0001) and 2q34–37 (P=0.009). Analysis weighted by study size confirmed linkage in these regions (3q26–27,P=0.0002; 2q34–37,P=0.014).Conclusions—The genetic regions 3q26–27 and 2q34–37 might contain susceptibility genes for CHD. Linkage to the 3q26-qter region has previously been shown in type 2 diabetes mellitus, metabolic syndrome, cholesterol concentration in LDL size fractions, and renal function in hypertensive subjects. The 2q34–37 region lies close to the type 2 diabetesNIDDM1locus. Both of these regions harbor several candidate genes involved in the homeostasis of glucose and lipid metabolism. These results are particularly intriguing, given the growing evidence of an association between CHD risk and metabolic abnormalities, such as insulin resistance, type 2 diabetes, abdominal obesity, and dyslipidemia.
Inhibition of Tumor Necrosis Factor-α–Induced SHP-2 Phosphatase Activity by Shear Stress
Authors: Lerner-Marmarosh Nicole , Yoshizumi Masanori , Che Wenyi , Surapisitchat James , Kawakatsu Hisaaki , Akaike Masashi , Ding Bo , Huang Qunhua , Yan Chen , Berk Bradford C. , Abe Jun-ichi 
Published: September 2003

Objectives—Atherosclerosis preferentially occurs in areas of turbulent flow, whereas laminar flow is atheroprotective. Inflammatory cytokines have been shown to stimulate adhesion molecule expression in endothelial cells that may promote atherosclerosis, in part, by stimulating c-JunN-terminal kinase (JNK) and nuclear factor (NF)-κB transcriptional activity.Methods and Results—Because Src kinase family and Src homology region 2-domain phosphatase-2 (SHP-2) may regulate JNK activation, we studied the effect of shear stress on endothelial inflammation and JNK. Human umbilical vein endothelial cells preexposed to flow showed decreased tumor necrosis factor (TNF)-α–induced c-Jun and NF-κB transcriptional activation. TNF-α–mediated JNK, c-Jun, and NF-κB activation required Src and SHP-2 activity. Shear stress significantly inhibited SHP-2 phosphatase activity without affecting TNF-α–induced Src family kinase activation. Because MEKK3 and Gab1 are critical for TNF-α–induced c-Jun and NF-κB activation, we determined the role of SHP-2 phosphatase activity in MEKK3 signaling. A catalytically inactive form of SHP-2 increased MEKK3/Gab1 interaction and inhibited MEKK3 (but not MEKK1)-mediated c-Jun and NF-κB activation.Conclusions—These results suggest that SHP-2 is a key mediator for the inhibitory effects of shear stress on TNF-α signaling in part via regulating MEKK3/Gab1 interaction, MEKK3 signaling, and subsequent adhesion molecule expression.
A retrospective 11-year analysis of obstetric patients with idiopathic thrombocytopenic purpura
Authors: Webert Kathryn E. , Mittal Richa , Sigouin Christopher , Heddle Nancy M. , Kelton John G. 
Published: September 2003

AbstractNumerous studies have examined the outcomes of infants born to mothers with idiopathic thrombocytopenic purpura (ITP). Fewer studies have discussed the morbidity of obstetric patients with ITP. We describe a retrospective study of 92 women with ITP during 119 pregnancies over an 11-year period. Most women had thrombocytopenia during pregnancy. At delivery, women in 98 pregnancies (89%) had platelet counts lower than 150 × 109/L; most had mild to moderate thrombocytopenia. For many, the pregnancy was uneventful; however, women had moderate to severe bleeding in 25 pregnancies (21.5%). Women in 37 pregnancies (31.1%) required treatment to increase platelet counts. During delivery, 44 women (37.3%) received epidural analgesia without complications, with most having a platelet count between 50 and 149 × 109/L. Most deliveries (82.4%) were vaginal. Bleeding was uncommon at delivery. Infant platelet counts at birth ranged from 12 to 436 × 109/L; 25.2% of infants had platelet counts lower than 150 × 109/L, and 9% had platelet counts lower than 50 × 109/L. Eighteen infants (14.6%) required treatment for hemostatic impairment. Two fetal deaths occurred. One was caused by hemorrhage. ITP in pregnancy carries a low risk, but mothers and infants may require therapy to raise their platelet counts. (Blood. 2003;102:4306-4311)