D J Fitzgerald

University College Dublin, Dublin, Leinster, Ireland

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Publications (271)1979.94 Total impact

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    Simone Marcone · Karen Haughton · Paul J Simpson · Orina Belton · Desmond J Fitzgerald
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    ABSTRACT: Milk-derived bioactive peptides retain many biological properties and have therapeutic effects in cardiovascular disorders such as atherosclerosis. Under inflammatory conditions the expression of endothelial cells adhesion molecules is induced, increasing monocyte adhesion to human vessel wall, a critical step in the pathogenesis of atherosclerosis. In the present work we explored the effects of milk-derived bioactive peptides on the expression of the inflammatory phenotype of human endothelial cells and their effects on monocyte adherence to endothelial cells. Treatment of endothelial cells with milk-derived hydrolysate inhibited their production of inflammatory proteins MCP-1 and IL-8 and expression of VCAM-1, ICAM-1 and E-selectin. Milk derived hydrolysate also attenuated the adhesion of human monocytes to activated endothelial cells. The effect was similar to that obtained in endothelial cells treated with troglitazone, a ligand of peroxisome proliferators-activator receptor-gamma (PPAR-γ). PPAR-γ is a transcription factor which when activated antagonises the pro-inflammatory capability of nuclear factor κB (NF-κB). We further examined whether the effects of milk-derived hydrolysates on endothelial cells may be mediated through NF-κB activation via a PPAR-γ dependent mechanism. The specific PPAR-γ inhibitor, GW9662 blocked the effects of the hydrolysate on the NF-κB-mediated chemokines and adhesion molecules expression in endothelial cells. These results suggest that milk-derived bioactive peptides work as anti-atherogenic agents through the inhibition of endothelial-dependent adhesive interactions with monocytes by inhibiting the NF-κB pathway through a PPAR-γ dependent mechanism.
    Full-text · Article · Dec 2015 · Journal of Inflammation
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    S Marcone · F Dervin · D J Fitzgerald
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    ABSTRACT: Antiplatelet agents represent the mainstay of acute coronary syndrome (ACS) therapy to prevent ischemic events and to improve safety in patients undergoing percutaneous coronary intervention. However, despite the availability of several drugs and the use of dual antiplatelet therapy, the pharmacological response is highly variable with a subset of patients continuing to experience recurrent thrombotic events, revealing a wide variability in platelet response to antiplatelet drugs. Several factors may explain this, including genetic variation and environmental factors. Here we look at the application of proteomic analysis, an approach that provides an integrated readout of these diverse influences. © 2015 International Society on Thrombosis and Haemostasis.
    Preview · Article · Jun 2015 · Journal of Thrombosis and Haemostasis
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    ABSTRACT: Conjugated linoleic acid (CLA) has the unique property of inducing regression of pre-established murine atherosclerosis. Understanding the mechanism(s) involved may help identify endogenous pathways that reverse human atherosclerosis. Here, we provide evidence that CLA inhibits foam cell formation via regulation of the nuclear receptor coactivator, peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α, and that macrophage PGC-1α plays a role in atheroprotection in vivo. PGC-1α was identified as a hub gene within a cluster in the aorta of the apoE(-/-) mouse in the CLA-induced regression model. PGC-1α was localized to macrophage/foam cells in the murine aorta where its expression was increased during CLA-induced regression. PGC-1α expression was also detected in macrophages in human atherosclerosis and was inversely linked to disease progression in patients with the disease. Deletion of PGC-1α in bone marrow derived macrophages promoted, whilst over expression of the gene inhibited foam cell formation. Importantly, macrophage specific deletion of PGC-1α accelerated atherosclerosis in the LDLR(-/-) mouse in vivo. These novel data support a functional role for PGC-1α in atheroprotection.
    Full-text · Article · Sep 2013 · EMBO Molecular Medicine
  • Simone Marcone · Desmond J Fitzgerald
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    ABSTRACT: 15-deoxy-delta12,14-prostaglandin J2 (15d-PGJ2) is an endogenous anti-inflammatory lipid derived from PGD2 . One potential mechanism for its activity is the covalent modification of cellular proteins, via a reactive α,β-unsaturated carbonyl group in its cyclopentenone ring, which in turn alters protein function. In order to identify the candidate target proteins covalently modified by 15d-PGJ2 in human aortic endothelial cell (EC), EC were treated with biotinylated-15d-PGJ2, the modified proteins extracted by Neutravidin affinity-purification and the proteins identified by LTQ Orbitrap mass spectrometer. Classification of the 358 identified proteins was performed using PANTHER classification system (www.pantherdb.org), showing that the proteins mapped to metabolic process, cellular process and transport activity. This protein data set highlights the potential for 15d-PGJ2 to covalently modify cellular proteins and provides a source of data that will aid further studies on the mechanism of action of this endogenous regulator of inflammation. This article is protected by copyright. All rights reserved.
    No preview · Article · Jul 2013 · Proteomics
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    ABSTRACT: Wnt signaling is involved in numerous aspects of vertebrate development and homeostasis, including the formation and function of blood cells. Here, we show that canonical and non-canonical Wnt signaling pathways are present and functional in megakaryocytes (MKs), with several Wnt effectors displaying MK-restricted expression. Using the CHRF288-11 cell line as a model for human MKs, the canonical Wnt3a signal was found to induce a time- and dose-dependent increase in β-catenin expression. β-catenin accumulation was inhibited by the canonical antagonist dickkopf-1 (DKK1) and by the non-canonical agonist Wnt5a. Whole genome expression analysis demonstrated that Wnt3a and Wnt5a regulated distinct patterns of gene expression in MKs, and revealed a further interplay between canonical and non-canonical Wnt pathways. Fetal liver cells derived from low-density-lipoprotein receptor-related protein 6-deficient mice (LRP6(-/-)), generated dramatically reduced numbers of MKs in culture of lower ploidy (2N and 4N) than wildtype controls, implicating LRP6-dependent Wnt signaling in MK proliferation and maturation. Finally, in wildtype mature murine fetal liver-derived MKs, Wnt3a potently induced proplatelet formation, an effect that could be completely abrogated by DKK1. These data identify novel extrinsic regulators of proplatelet formation, and reveal a profound role for Wnt signaling in platelet production.
    Full-text · Article · Nov 2012 · Blood
  • Monica de Gaetano · Eugene Dempsey · Simone Marcone · Desmond J Fitzgerald · Orina Belton
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    ABSTRACT: Recruitment of monocytes to the damaged endothelium characterizes the early stages of atherosclerosis. Conjugated linoleic acids (CLA) are a group of naturally occurring fatty acids which inhibit the progression and induce regression of pre-established atherosclerosis. We have previously shown that CLA inhibits human peripheral blood monocyte (HPBMC) migration. Here we demonstrate that CLA suppresses adhesion of monocytes to endothelial cells, via inhibition of β2 integrins. We further show that CLA suppresses the CXCR4 signalling pathway thus inhibiting crawling of monocytes towards CXCL12 chemokine. HPBMCs were treated with 10uM of CLA isomers (c9,t11-CLA and t10,c12-CLA), a CLA blend (80:20, c9t,11:t10,c12), control lipids and 5uM of PPAR{gamma} agonist (troglitazone) prior to adhesion to HAECs. c9,t11-CLA and CLA blend treatment inhibited monocyte adhesion to HAECs (63±3%, p<0.01 and 68±3%, p<0.01, respectively). Furthermore, c9,t11-CLA and CLA blend inhibited CD18, the β chain of β2 integrin, mRNA (48±14%, p<0.05 and 35±3%, p<0.001) and protein expression (44±13%, p<0.05, and 35±3%, p<0.001) via a PPAR{gamma}[[Unable to Display Character: ]]dependent mechanism. Flow cytometry analysis showed that c9,t11-CLA and CLA blend decreased external surface expression of both β chain (10±4%, p<0.05 and 20±5%, p<0.01), and α subunits (CD11a, 13±6%, p<0.05 and 30±5%, p<0.01; CD11b, 8±3%, p<0.05 and 27±7%, p<0.01), suggesting that CLA’s effect on CD18 transcription results in dysfunctional αβ complex formation, altering expression of LFA-1 and Mac-1 integrins. Furthermore, c9,t11-CLA and CLA blend almost completely abolished (by 82% and 89%, p<0.001) adhesion of monocytes to ICAM-1. Immunocytochemistry of adherent cells further confirmed the inhibition of cell spreading. Importantly, CLA suppresses monocyte response to chemoattraction, preventing crawling of cells through a reduction, of CXCR4 expression (c9,t11-CLA, 47±10%, p<0.05; CLA blend, 33±5%, p<0.01). Our findings suggest that CLA inhibits monocyte recruitment by suppressing their sensitivity to chemokines and by inhibiting their ability to firmly attach to ICAM-1.
    No preview · Conference Paper · Nov 2012
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    ABSTRACT: Conjugated linoleic acid (CLA) induces regression of preestablished atherosclerosis in the ApoE(-/-) mouse. Understanding the mechanisms involved may help in identifying novel pathways associated with the regression of human disease. Animals were administered a 1% cholesterol diet for 12 wk, with 1% CLA supplementation from wk 8 to 12. ApoE(-/-) mice fed only the 1% cholesterol diet for 12 wk were employed as controls. Transcriptomic analysis of mouse aorta showed that many of the components of the IL-10 signaling pathway were modified during CLA-induced regression. Real-time PCR and Western blot analysis showed increased IL-10 receptor expression, phosphorylation of STAT3, and downstream target gene expression in the aorta, alongside an increase in serum IL-10 (79.8±22.4 vs. 41.9±5.5 pg/ml, n=10; P<0.01). CLA -supplementation also increased IL-10 production in bone marrow-derived macrophages (143.6±28.6 vs. 94±5.6 pg/ml, n=5; P<0.05). To explore the mechanisms for altered IL-10 production, we examined the profile of monocyte/macrophage phenotype in the vessel wall, bone marrow, and spleen. CLA increased macrophage polarization toward an anti-inflammatory M2 phenotype in vivo, increasing the population of Ly6C(lo) monocytes (29 vs. 77±14, n=5, P < 0.05) in the aorta. CLA had similar effects on monocytes/macrophages differentiated from marrow-derived progenitor cells and on splenocytes. The induction of IL-10 on CLA supplementation in this model may reflect a systemic alteration toward an anti-inflammatory phenotype, which, in turn promotes increased vascular infiltration by Ly6C(lo) monocytes. These cells may contribute to CLA-induced disease regression.-McCarthy, C., Duffy, M. M., Mooney, D., James, W. G., Griffin, M. D., Fitzgerald, D. J., Belton, O. IL-10 mediates the immunoregulatory response in conjugated linoleic acid-induced regression of atherosclerosis.
    Full-text · Article · Oct 2012 · The FASEB Journal
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    ABSTRACT: Here we provide evidence that WNT-3a modulates platelet function by regulating the activity of four key GTPase proteins: Rap1, Cdc42, Rac1 and RhoA. We observe WNT-3a to differentially regulate small GTPase activity in platelets, promoting the GDP-bound form of Rap1b to inhibit integrin-α(IIb)β(3) adhesion, while concomitantly increasing Cdc42 and Rac1-GTP levels thereby disrupting normal platelet spreading. We demonstrate that Daam-1 interacts with Dishevelled upon platelet activation, which correlates with increased RhoA-GTP levels. Upon pre-treatment with WNT-3a, this complex disassociates, concurrent with a reduction in RhoA-GTP. Together these data implicate WNT-3a as a novel upstream regulator of small GTPase activity in platelets.
    Full-text · Article · Jun 2012 · FEBS letters
  • Patricia B. Maguire · Brian M. Steele · Desmond J. Fitzgerald
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    ABSTRACT: Unbiased proteomic analyses of cell fractions, interactomes and protein modifications coupled with more targeted approaches are adding to an impressive database of the signalling pathways in platelets. In addition to the well characterized receptors that are known to exist on the platelet surface, platelet proteomic studies continue to expose novel transmembrane proteins including CD148, CLEC-2, Eph kinases and Ephrins, Frizzled-4 and -6, G6b, HIP-55, HSP47, LRP5/6 and PEAR-1. In turn identification of novel platelet receptors has led to the discovery of new platelet signaling pathways such as the collagen/CLEC-2 receptor pathway, as well as the canonical WNT pathway. This review focuses on the canonical WNT pathway, providing background information to WNT ligands, receptors and signalling pathways and then focusing on canonical WNT signalling in anucleate platelets, where the suppression of platelet activity and adhesion by its ligand, Wnt-3a has recently been demonstrated.
    No preview · Article · Oct 2011 · Current Proteomics
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    ABSTRACT: Atopaxar (E5555) is a reversible protease-activated receptor-1 thrombin receptor antagonist that interferes with platelet signaling. The primary objective of the Lessons From Antagonizing the Cellular Effects of Thrombin-Acute Coronary Syndromes (LANCELOT—ACS) trial was to evaluate the safety and tolerability of atopaxar in patients with ACS. Six hundred and three subjects were randomized within 72 hours of non-ST-elevation ACS to 1 of 3 doses of atopaxar (400-mg loading dose followed by 50, 100, or 200 mg daily) or matching placebo. The incidence of Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) major or minor bleeding did not differ significantly between the combined atopaxar and placebo groups (3.08% versus 2.17%, respectively; P=0.63), and there was no dose-related trend (P=0.80). The incidence of CURE major bleeding was numerically higher in the atopaxar group compared with the placebo group (1.8% versus 0%; P=0.12). The incidence of cardiovascular death, myocardial infarction, stroke, or recurrent ischemia was similar between the atopaxar and placebo arms (8.03% versus 7.75%; P=0.93). The incidence of CV death, MI, or stroke was 5.63% in the placebo group and 3.25% in the combined atopaxar group (P=0.20). Dose-dependent trends for efficacy were not seen. Atopaxar significantly reduced ischemia on continuous ECG monitoring (Holter) at 48 hours compared with placebo (relative risk, 0.67; P=0.02). Transient dose-dependent transaminase elevation and relative QTc prolongation were observed with the highest doses of atopaxar. In patients after ACS, atopaxar significantly reduced early ischemia on Holter monitoring without a significant increase in major or minor bleeding. Larger trials are required to fully establish the efficacy and safety of atopaxar. URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00548587.
    Full-text · Article · May 2011 · Circulation
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    ABSTRACT: Background-Thrombin is a key mediator of platelet activation. Atopaxar is a reversible protease-activated receptor-1 antagonist that interferes with thrombin-mediated platelet effects. The phase II Lessons From Antagonizing the Cellular Effect of Thrombin-Coronary Artery Disease (LANCELOT-CAD) trial examined the safety and tolerability of prolonged therapy with atopaxar in subjects with CAD. Methods and Results-Subjects with a qualifying history were randomized in a double-blind fashion to 3 dosing regimens of atopaxar (50, 100, or 200 mg daily) or matching placebo for 24 weeks and followed up for an additional 4 weeks. The key safety end points were bleeding according to the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) and Thrombolysis in Myocardial Infarction (TIMI) classifications. Secondary objectives included platelet aggregation and major adverse cardiac events. Seven hundred and twenty subjects were randomized. Overall bleeding rates tended to be higher with atopaxar compared with placebo by CURE criteria (placebo, 0.6%; atopaxar, 3.9%; relative risk, 6.82, P = 0.03; 50 mg, 3.9%; 100 mg, 1.7%; 200 mg, 5.9%; P for trend = 0.01) and TIMI criteria (placebo, 6.8%; atopaxar, 10.3%; relative risk, 1.52, P = 0.17; 50 mg, 9.9%; 100 mg, 8.1%; 200 mg, 12.9%; P for trend = 0.07). There was no difference in major bleeding. Major adverse cardiac events were numerically lower in the atopaxar subjects. All atopaxar regimens achieved high levels of platelet inhibition. A transient elevation in liver transaminases and dose-dependent QTc prolongation without apparent complications were observed in higher-dose atopaxar treatment groups. Conclusions-In this dose-ranging study of patients with CAD, treatment with atopaxar resulted in platelet inhibition, more minor bleeding, and numerically but not statistically fewer ischemic events. Larger-scale trials are needed to determine whether these patterns translate into clinically meaningful effects.
    Preview · Article · May 2011 · Circulation
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    ABSTRACT: Within the healthy population, there is substantial, heritable, and interindividual variability in the platelet response. We explored whether a proportion of this variability could be accounted for by interindividual variation in gene expression. Through a correlative analysis of genome-wide platelet RNA expression data from 37 subjects representing the normal range of platelet responsiveness within a cohort of 500 subjects, we identified 63 genes in which transcript levels correlated with variation in the platelet response to adenosine diphosphate and/or the collagen-mimetic peptide, cross-linked collagen-related peptide. Many of these encode proteins with no reported function in platelets. An association study of 6 of the 63 genes in 4235 cases and 6379 controls showed a putative association with myocardial infarction for COMMD7 (COMM domain-containing protein 7) and a major deviation from the null hypo thesis for LRRFIP1 [leucine-rich repeat (in FLII) interacting protein 1]. Morpholino-based silencing in Danio rerio identified a modest role for commd7 and a significant effect for lrrfip1 as positive regulators of thrombus formation. Proteomic analysis of human platelet LRRFIP1-interacting proteins indicated that LRRFIP1 functions as a component of the platelet cytoskeleton, where it interacts with the actin-remodeling proteins Flightless-1 and Drebrin. Taken together, these data reveal novel proteins regulating the platelet response.
    No preview · Article · Nov 2010 · Blood
  • Cathal McCarthy · Declan Mooney · Desmond Fitzgerald · Orina Belton

    No preview · Conference Paper · Nov 2010
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    ABSTRACT: We have previously shown that CLA induces regression of pre-established atherosclerotic lesions in apoE(-/-) mice. CLA is a known ligand of peroxisome proliferator activated receptors (PPARs) and it is postulated that CLA mediates its atheroprotective effects through activation of PPARs. Earlier work in our group identified the monocyte/macrophage cell as the primary cellular target of CLA. In this study we identified novel genes regulated by CLA during the regression of atherosclerosis and characterised a role for one of these, SorLA. SorLA is a member of the vacuolar protein sorting 10 protein (Vps10p) domain receptor family, which has structural homology with the LDLR family. Expression of SorLA was identified with its Vps10p family member Sort1 by transcriptomic analysis of murine aorta following CLA-induced regression of atherosclerosis. Decreased expression of both receptors was confirmed by real-time PCR in the aorta of CLA-supplemented mice. SorLA protein expression was predominantly localised to monocyte/macrophage cells in the vasculature by immunohistochemistry. CLA and the PPAR-γ agonists, troglitazone, and 15-deoxy-prostaglandin (PG) J(2), decreased protein and RNA expression of SorLA in THP-1 monocytes; while pre-treatment with a PPAR-γ antagonist established a PPAR-γ dependent role for CLA regulation of SorLA. CLA inhibits monocyte migration. Consistent with a role for SorLA in mediating this response, overexpression of SorLA increased migration of THP-1 monocytes to monocyte chemoattractant protein-1 with a coincident increase in UPAR expression. CLA may mediate its atheroprotective effects in part through reduced expression of SorLA and a resulting inhibition of monocyte migration in vitro.
    Full-text · Article · Oct 2010 · Atherosclerosis
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    A O Maree · C Vangjeli · H Jneid · J Ryan · D Cox · C P Cannon · D C Shields · D J Fitzgerald
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    ABSTRACT: Variability in platelet response to antiplatelet drugs is heritable. A common single base substitution (825C>T) in the G-protein beta polypeptide 3 (GNB3) gene leads to alternative splicing (41-amino-acid deletion) of the human G-protein beta3 (Gbeta3) subunit. This truncated protein carried by GNB3 T allele carriers is linked to coronary artery disease and implicated as a genetic marker of drug response. Large studies of Caucasians associate T allele carriage with lower platelet reactivity. To evaluate whether the GNB3 genotype would predispose to bleeding in patients treated with a GPIIb/IIIa receptor antagonist. GNB3 genotype distribution was determined in DNA samples from patients in the orbofiban in patients with unstable coronary syndromes-thrombolysis in myocardial infarction (OPUS-TIMI) 16 genetic sub-study. Impact of genotype on the bleeding endpoint and the composite primary endpoint of death, myocardial infarction (MI), re-hospitalization for ischemia and urgent revascularization was estimated in the treatment and placebo arm. Out of 887 patients, 45.1% carried the GNB3 CC genotype, 44.5% CT and 10.4% TT. Interaction between T allele carriership and treatment for bleeding was significant (P = 0.008). This reflects the fact that GNB3 non-T carriers treated with orbofiban had no bleeding effect compared with placebo (RR = 0.92, 95% CI 0.55-1.55) whereas T carriers did (RR = 2.62, 95% CI 1.58-4.35, P < 0.001). Interaction between T allele carriership and treatment was not significant for the primary endpoint (P = 0.18) or MI (P = 0.69). The GNB3 T allele significantly increased bleeding in patients treated with the platelet antagonist orbofiban. Our findings suggest that risk of bleeding associated with an antiplatelet agent is heritable and may be dissociated from risk of thrombosis.
    Full-text · Article · May 2010 · Journal of Thrombosis and Haemostasis
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    ABSTRACT: The signaling molecule 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) has been described as the “anti-inflammatory prostaglandin.” Here we show that substrates of the nuclear export receptor CRM1 accumulate in the nucleus in the presence of 15d-PGJ2, identifying this prostaglandin as a regulator of CRM1-dependent nuclear protein export that can be produced endogenously. Like leptomycin B (LMB), an established fungal CRM1-inhibitor, 15d-PGJ2 reacts with a conserved cysteine residue in the CRM1 sequence. This covalent modification prevents the formation of nuclear export complexes. Cells that are transfected with mutant CRM1 (C528S) are resistant to the inhibitory effects of LMB and 15d-PGJ2, demonstrating that the same single amino acid is targeted by the two compounds. Inhibition of the CRM1 pathway by endogenously produced prostaglandin and/or exogenously applied 15d-PGJ2 may contribute to its anti-inflammatory, anti-proliferative, and anti-viral effects.
    Preview · Article · May 2010 · Journal of Biological Chemistry
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    ABSTRACT: Supplementary Table 1: Peptide and protein identification. In order to identify proteins present in the collected fractions, each lane from the SDS-PAGE gel of fractionated platelet relaseate was divided into 32 bands, digested with trypsin and subjected to LC-MS/MS. The resulting spectra were searched using SEQUEST against the International Protein Index database in order to identify matching peptides. Protein Prophet was used to filter identifications. Supplementary Table 2: Protein abundance. Spectral counts (counts of tandem mass spectrometry events leading to productive protein identification) were calculated for all proteins, giving an estimate of protein abundance in each IEC fraction.
    Preview · Dataset · Mar 2010
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    ABSTRACT: Proteomic approaches have proven powerful at identifying large numbers of proteins, but there are fewer reports of functional characterization of proteins in biological tissues. Here, we describe an experimental approach that fractionates proteins released from human platelets, linking bioassay activity to identity. We used consecutive orthogonal separation platforms to ensure sensitive detection: (a) ion-exchange of intact proteins, (b) SDS-PAGE separation of ion-exchange fractions and (c) HPLC separation of tryptic digests coupled to electrospray tandem mass spectrometry. Migration of THP-1 monocytes in response to complete or fractionated platelet releasate was assessed and located to just one of the forty-nine ion-exchange fractions. Over 300 proteins were identified in the releasate, with a wide range of annotated biophysical and biochemical properties, in particular platelet activation, adhesion, and wound healing. The presence of PEDF and involucrin, two proteins not previously reported in platelet releasate, was confirmed by western blotting. Proteins identified within the fraction with monocyte promigratory activity and not in other inactive fractions included vimentin, PEDF, and TIMP-1. We conclude that this analytical platform is effective for the characterization of complex bioactive samples.
    Full-text · Article · Mar 2010 · BioMed Research International
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    ABSTRACT: Wnts regulate important intracellular signaling events, and dysregulation of the Wnt pathway has been linked to human disease. Here, we uncover numerous Wnt canonical effectors in human platelets where Wnts, their receptors, and downstream signaling components have not been previously described. We demonstrate that the Wnt3a ligand inhibits platelet adhesion, activation, dense granule secretion, and aggregation. Wnt3a also altered platelet shape change and inhibited the activation of the small GTPase RhoA. In addition, we found the Wnt-beta-catenin signaling pathway to be functional in platelets. Finally, disruption of the Wnt Frizzled 6 receptor in the mouse resulted in a hyperactivatory platelet phenotype and a reduced sensitivity to Wnt3a. Taken together our studies reveal a novel functional role for Wnt signaling in regulating anucleate platelet function and may provide a tractable target for future antiplatelet therapy.
    Full-text · Article · Nov 2009 · Proceedings of the National Academy of Sciences
  • Louise K Brennan · Brian H Harte · Desmond J Fitzgerald · Connail R McCrory
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    ABSTRACT: Nonsteroidal anti-inflammatory drugs with a selective cyclooxygenase-2 (COX-2) inhibitory profile are effective analgesics in the postoperative period. This implies that surgery induces COX-2 biosynthesis. We examined whether peripheral surgical trauma can induce COX-2 expression in the rat cervical spinal cord. Sprague-Dawley rats were divided into 2 groups. The control group underwent general anesthesia but had no surgery. The surgical group underwent general anesthesia and surgical exposure of neck structures. After 14 days, the animals were euthanized, and a section of cervical spinal cord was taken to identify COX-1 and COX-2 expression by immunohistochemical analysis. Two independent blinded observers analyzed the slides. Analysis of COX-1 protein expression revealed homogenous staining in glial cells in all regions of the cervical spinal cord examined. There was no difference in expression between the control and surgical groups. However, whereas the control group demonstrated minimal COX-2 expression, the surgical group showed extensive neuronal and glial cell cytoplasmic COX-2 expression. This study demonstrates that surgery induces COX-2 expression in the rat cervical spinal cord. This could provide a scientific rationale for the use of selective COX-2 inhibitors as analgesics in the postoperative period.
    No preview · Article · Nov 2009 · Regional anesthesia and pain medicine

Publication Stats

9k Citations
1,979.94 Total Impact Points


  • 1995-2015
    • University College Dublin
      • • School of Biomolecular and Biomedical Science
      • • School of Medicine & Medical Science
      Dublin, Leinster, Ireland
  • 1982-2009
    • Royal College of Surgeons in Ireland
      • Department of Clinical Pharmacology
      Dublin, Leinster, Ireland
  • 2006-2007
    • Harvard University
      Cambridge, Massachusetts, United States
    • Royal College of Surgeons of Edinburgh
      Edinburgh, Scotland, United Kingdom
  • 1999-2005
    • St. James's Hospital
      Dublin, Leinster, Ireland
  • 1998-2005
    • Beaumont Hospital
      Dublin, Leinster, Ireland
    • Clinical pharmacology of Miami
      Miami, Florida, United States
  • 2004
    • Baylor College of Medicine
      Houston, Texas, United States
    • National University of Ireland, Galway
      • National Diagnostics Centre
      Gaillimh, Connaught, Ireland
  • 2003
    • St Luke's General Hospital Carlow / Kilkenny
      Kilkenny, Leinster, Ireland
  • 2001-2003
    • University of Nottingham
      Nottigham, England, United Kingdom
  • 1996-2003
    • University of Pennsylvania
      • Department of Medicine
      Philadelphia, Pennsylvania, United States
  • 2002
    • The University of Sheffield
      • School of Clinical Dentistry
      Sheffield, England, United Kingdom
    • Trinity College
      Hartford, Connecticut, United States
  • 1994
    • The Adelaide and Meath Hospital Ireland
      Dublin, Leinster, Ireland
  • 1992-1993
    • Mater Misericordiae University Hospital
      • Department of Ophthalmology
      Dublin, Leinster, Ireland
  • 1984-1991
    • Vanderbilt University
      • • Division of Clinical Pharmacology
      • • Division of Pediatric Cardiology
      Нашвилл, Michigan, United States