Publications
165 results found
Khamis R, Woollard K, Kojima C, et al., 2014, A novel immunoglobulin G autoantibody against a cryptic epitope in low density lipoprotein (LDL) revealed in atherosclerosis
Khamis R, Woollard K, Boyle JJ, et al., 2014, A Novel Immunoglobulin G Autoantibody Against a Cryptic Epitope in Low Density Lipoprotein Induces Macrophage Tumour Necrosis Factor Release, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Amini N, Boyle JJ, Moers B, et al., 2014, Requirement of JNK1 for endothelial cell injury in atherogenesis, Atherosclerosis, Vol: 235, Pages: 613-618, ISSN: 1879-1484
ObjectiveThe c-Jun N-terminal kinase (JNK) family regulates fundamental physiological processes including apoptosis and metabolism. Although JNK2 is known to promote foam cell formation during atherosclerosis, the potential role of JNK1 is uncertain. We examined the potential influence of JNK1 and its negative regulator, MAP kinase phosphatase-1 (MKP-1), on endothelial cell (EC) injury and early lesion formation using hypercholesterolemic LDLR−/− mice.Methods and resultsTo assess the function of JNK1 in early atherogenesis, we measured EC apoptosis and lesion formation in LDLR−/− or LDLR−/−/JNK1−/− mice exposed to a high fat diet for 6 weeks. En face staining using antibodies that recognise active, cleaved caspase-3 (apoptosis) or using Sudan IV (lipid deposition) revealed that genetic deletion of JNK1 reduced EC apoptosis and lesion formation in hypercholesterolemic mice. By contrast, although EC apoptosis was enhanced in LDLR−/−/MKP-1−/− mice compared to LDLR−/− mice, lesion formation was unaltered.ConclusionWe conclude that JNK1 is required for EC apoptosis and lipid deposition during early atherogenesis. Thus pharmacological inhibitors of JNK may reduce atherosclerosis by preventing EC injury as well as by influencing foam cell formation.
Bao N, Le L, Naase H, et al., 2014, Sulforaphane pretreatment prevents systemic inflammation and renal injury in response to cardiopulmonary bypass, JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY, Vol: 148, Pages: 690-+, ISSN: 0022-5223
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- Citations: 17
Alrashed F, Calay D, Thornton C, et al., 2014, Celecoxib-mediated activation of an AMPK-CREB-Nrf2 dependent pathway: a novel mechanism for endothelial cytoprotection in chronic systemic inflammation, 3rd Congress of the ESC-Council-on-Basic-Cardiovascular-Science on Frontiers in Cardio Vascular Biology, Publisher: OXFORD UNIV PRESS, ISSN: 0008-6363
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- Citations: 2
Khamis RY, Woollard KJ, Hyde GD, et al., 2014, DEVELOPMENT OF WHOLE BODY AND INTRAVASCULAR NEAR-INFRARED OPTICAL MOLECULAR IMAGING OF MARKERS OF PLAQUE VULNERABLITY IN ATHEROSCLEROSIS, Annual Conference of the British-Cardiovascular-Society
Khamis R, Woollard K, Boyle J, et al., 2014, A NOVEL IMMUNOGLOBULIN G AUTOANTIBODY AGAINST LOW DENSITY LIPOPROTEIN (LDL) WITH PATHOGENIC FUNCTIONS, Annual Conference of the British-Cardiovascular-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A121-A121, ISSN: 1355-6037
Thornton C, Alrashed F, Calay D, et al., 2014, METHOTREXATE: A NOVEL MECHANISM FOR VASCULOPROTECTION IN CHRONIC SYSTEMIC INFLAMMATION, 15th Annual European Congress of Rheumatology (EULAR), Publisher: BMJ PUBLISHING GROUP, Pages: 363-364, ISSN: 0003-4967
Hamdulay SS, Wang B, Calay D, et al., 2014, Synergistic therapeutic vascular cytoprotection against complement- mediated injury induced via a PKC alpha-, AMPK-, and CREB- dependent pathway, Journal of Immunology, Vol: 192, Pages: 4316-4327, ISSN: 1550-6606
Endothelial injury and dysfunction precede accelerated arterial disease in allograft vasculopathy and systemic autoimmune diseases and involve pathogenic Abs and complement. Recent reports suggest that switching to rapamycin from calcineurin antagonists reduces posttransplant vasculopathy and prolongs survival following cardiac transplantion. The majority of these patients also receive statin therapy. We examined potential mechanisms underlying this protective response in human endothelial cells and identified synergy between rapamycin and atorvastatin. Mechanistically, atorvastatin and rapamycin activated a protein kinase Cα, AMP-activated kinase, and CREB-dependent vasculoprotective pathway, which induced decay-accelerating factor (DAF) promoter activity via binding to the cAMP response element, mutation of which attenuated promoter activity. This response significantly increased endothelial cell surface DAF and enhanced protection against complement-mediated injury. Synergy with rapamycin was reproduced by simvastatin, whereas combining atorvastatin with cyclosporine or mycophenolate in place of rapamycin was ineffective. Importantly, synergy was reproduced in vivo, in which only atorvastatin and rapamycin therapy in combination was sufficient to induce DAF on murine aortic endothelium. We believe this pathway represents an important therapeutically inducible vasculoprotective mechanism for diseases mediated by pathogenic Abs and complement, including posttransplant vasculopathy and systemic lupus erythematosus. Although our study focuses on the vascular endothelium, the findings are likely to be broadly applicable, given the diverse cellular expression of DAF.
Thornton C, Al-Rashed F, Calay D, et al., 2014, METHOTREXATE: A NOVEL MECHANISM FOR VASCULOPROTECTION IN CHRONIC SYSTEMIC INFLAMMATION, Annual Meeting of the British-Society-for-Rheumatology and British-Health-Professionals-in-Rheumatology, Publisher: OXFORD UNIV PRESS, Pages: 35-35, ISSN: 1462-0324
Wan X, Huo Y, Johns M, et al., 2014, HEME AND METFORMIN COORDINATE HUMAN AND MURINE MACROPHAGE HEME OXYGENASE 1 EXPRESSION WITH FOAM CELL RESISTANCE PARTLY VIA ADENOSINE MONOPHOSPHATE KINASE AND ACTIVATING TRANSCRIPTION FACTOR 1 (AMPK-ATF1), Autumn Meeting of the British-Atherosclerosis-Society (BAS), Publisher: ELSEVIER IRELAND LTD, Pages: E4-E4, ISSN: 0021-9150
Wan X, Huo Y, Johns M, et al., 2013, 5′-AMP-Activated Protein Kinase-Activating Transcription Factor 1 Cascade Modulates Human Monocyte-Derived Macrophages to Atheroprotective Functions in Response to Heme or Metformin, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 33, Pages: 2470-2480, ISSN: 1079-5642
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- Citations: 35
Khamis R, Woollard K, Chang SH, et al., 2013, The Near Infra-Red (NIRF) molecular imaging of oxidised LDL in atherosclerosis with the native autoantibody LO1, and its molecularly expressed cysteine-tagged Fab construct (LO1-Fab-cys), Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 29-29, ISSN: 0195-668X
Khamis R, Woollard K, Granger D, et al., 2013, IMAGING BEYOND THE LUMEN: NEAR INFRA-RED IN VIVO MOLECULAR IDENTIFICATION OF OXIDISED LDL IN ATHEROSCLEROSIS USING MAB LO1, AND THE GENERATION AND DEVELOPMENT OF ITS MOLECULARLY EXPRESSED CYSTEINE-TAGGED CHIMERIC FAB CONSTRUCT (LO1-FAB-CYS), Annual Conference of the British-Cardiovascular-Society (BCS), Publisher: BMJ PUBLISHING GROUP, ISSN: 1355-6037
Luong L, Fragiadaki M, Smith J, et al., 2013, Cezanne Regulates Inflammatory Responses to Hypoxia in Endothelial Cells by Targeting TRAF6 for Deubiquitination., Circ Res
Rationale: Hypoxia followed by reoxygenation promotes inflammation by activating NF-κB transcription factors in endothelial cells (EC). This process involves modification of the signalling intermediary TRAF6 with polyubiquitin chains. Thus cellular mechanisms that suppress TRAF6 ubiquitination are potential therapeutic targets to reduce inflammation in hypoxic tissues. Objective: In this study, we tested the hypothesis that endothelial activation in response to hypoxia-reoxygenation can be influenced by Cezanne, a deubiquitinating enzyme that cleaves ubiquitin from specific modified proteins. Methods and Results: Studies of cultured endothelial cells (EC) demonstrated that hypoxia (1% oxygen) induced Cezanne via p38 MAP kinase-dependent transcriptional and post-transcriptional mechanisms. Hypoxia-reoxygenation had minimal effects on pro-inflammatory signalling in unmanipulated EC but significantly enhanced Lys-63 polyubiquitination of TRAF6, activation of NF-κB and expression of inflammatory genes following silencing of Cezanne. Thus although hypoxia primed cells for inflammatory activation it simultaneously induced Cezanne which impeded signalling to NF-κB by suppressing TRAF6 ubiquitination. Similarly, ischemia induced Cezanne in the murine kidney in vascular EC, glomerular EC, podocytes and epithelial cells, and genetic deletion of Cezanne enhanced renal inflammation and injury in murine kidneys exposed to ischemia followed by reperfusion. Conclusions: We conclude that inflammatory responses to ischemia are controlled by a balance between ubiquitination and deubiquitination and that Cezanne is a key regulator of this process. Our observations have important implications for therapeutic targeting of inflammation and injury during ischemia-reperfusion.
Landis RC, Philippidis P, Domin J, et al., 2013, Haptoglobin Genotype-Dependent Anti-Inflammatory Signaling in CD163(+) Macrophages., International Journal of Inflammation, Vol: 2013, ISSN: 2042-0099
Intraplaque hemorrhage causes adaptive remodelling of macrophages towards a protective phenotype specialized towards handling iron and lipid overload, denoted Mhem. The Mhem phenotype expresses elevated levels of hemoglobin (Hb) scavenger receptor, CD163, capable of endocytosing pro-oxidant free Hb complexed to acute phase protein haptoglobin (Hp). It is notable that individuals homozygous for the Hp 2 allele (a poorer antioxidant) are at increased risk of cardiovascular disease compared to the Hp 1 allele. In this study, we examined whether scavenging of polymorphic Hp:Hb complexes differentially generated downstream anti-inflammatory signals in cultured human macrophages culminating in interleukin (IL)-10 secretion. We describe an anti-inflammatory signalling pathway involving phosphatidylinositol-3-kinase activation upstream of Akt phosphorylation (pSer473Akt) and IL-10 secretion. The pathway is mediated specifically through CD163 and is blocked by anti-CD163 antibody or phagocytosis inhibitor. However, levels of pSer473Akt and IL-10 were significantly diminished when scavenging polymorphic Hp2-2:Hb complexes compared to Hp1-1:Hb complexes (P < 0.05). Impaired anti-inflammatory macrophage signaling through a CD163/pAkt/IL-10 axis may thus represent a possible Hp2-2 disease mechanism in atherosclerosis.
Haskard DO, Boyle JJ, Evans PC, et al., 2013, Cytoprotective Signaling and Gene Expression in Endothelial Cells and MacrophagesLessons for Atherosclerosis, MICROCIRCULATION, Vol: 20, Pages: 203-216, ISSN: 1073-9688
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- Citations: 8
Johns M, Carling D, Piper EL, et al., 2012, An Adenosine Monophosphate Activated Protein Kinase / Activating Transcription Factor-1 Cascade Initiates Commitment to Mhem Atheroprotective Macrophages in Response to Heme or Metformin, CIRCULATION, Vol: 126, ISSN: 0009-7322
Khamis RY, Chang S-H, Boyle JJ, et al., 2012, THE GENERATION AND CHARACTERISATION OF LO1: A UNIQUE IGG MONOCLONAL NATURAL ANTIBODY AGAINST OXIDISED LDL (OXLDL), Joint Spring Meeting of the British-Society-for-Cardiovascular-Research (BSCR) and British-Atherosclerosis-Society (BAS), Publisher: BMJ PUBLISHING GROUP, Pages: A6-A6, ISSN: 1355-6037
Neilan M, Zhang X, Steiner T, et al., 2012, TILRR FUNCTIONAL MUTANTS SELECTIVELY INHIBIT INFLAMMATORY AND ANTI-APOPTOTIC RESPONSES, Joint Spring Meeting of the British-Society-for-Cardiovascular-Research (BSCR) and British-Atherosclerosis-Society (BAS), Publisher: BMJ PUBLISHING GROUP, Pages: A6-A6, ISSN: 1355-6037
Dumont O, Mylroie H, Bauer A, et al., 2012, Protein kinase Cε activity induces anti-inflammatory and anti-apoptotic genes via an ERK1/2-and NF-κB-dependent pathway to enhance vascular protection, BIOCHEMICAL JOURNAL, Vol: 447, Pages: 193-204, ISSN: 0264-6021
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- Citations: 10
Boyle JJ, 2012, Heme and haemoglobin direct macrophage Mhem phenotype and counter foam cell formation in areas of intraplaque haemorrhage, CURRENT OPINION IN LIPIDOLOGY, Vol: 23, Pages: 453-461, ISSN: 0957-9672
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- Citations: 50
Boyle JJ, Christou I, Iqbal MB, et al., 2012, Solid-Phase Immunoglobulins IgG and IgM Activate Macrophages with Solid-Phase IgM Acting via a Novel Scavenger Receptor A Pathway, AMERICAN JOURNAL OF PATHOLOGY, Vol: 181, Pages: 347-361, ISSN: 0002-9440
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- Citations: 10
Chang S-H, Johns M, Boyle JJ, et al., 2012, Model IgG Monoclonal Autoantibody-Anti-Idiotype Pair for Dissecting the Humoral Immune Response to Oxidized Low Density Lipoprotein, HYBRIDOMA, Vol: 31, Pages: 87-98, ISSN: 1554-0014
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- Citations: 10
Haskard D, Talat M, Lewis M, et al., 2011, Bifunctional roles of complement and antibodies in atherosclerosis, Annual Congress of the British-Society-for-Immunology, Publisher: WILEY-BLACKWELL, Pages: 16-16, ISSN: 0019-2805
Boyle JJ, Johns M, Kampfer T, et al., 2011, Activating Transcription Factor 1 Directs Mhem Atheroprotective Macrophages Through Coordinated Iron Handling and Foam Cell Protection., Circulation Research
Rationale:Intraplaque hemorrhage (IPH) drives atherosclerosis through the dual metabolic stresses of cholesterol-enriched erythrocyte membranes and pro-oxidant heme/iron. When clearing tissue hemorrhage, macrophages are typically seen storing either iron or lipid. We have recently defined hemorrhage-associated macrophages (HA-mac) as a plaque macrophage population that responds adaptively to IPH.Objective:This study aimed to define the key transcription factor(s) involved in HO-1 induction by heme.Methods and Results:To address this question, we used microarray analysis and transfection with siRNA and plasmids. To maintain physiological relevance, we focused on human blood-derived monocytes. We found that heme stimulates monocytes through induction of activating transcription factor 1 (ATF-1). ATF-1 coinduces heme oxygenase-1 (HO-1) and Liver X receptor beta (LXR-β). Heme-induced HO-1 and LXR-β were suppressed by knockdown of ATF-1, and HO-1 and LXR-β were induced by ATF-1 transfection. ATF-1 required phosphorylation for full functional activity. Expression of LXR-β in turn led to induction of other genes central to cholesterol efflux, such as LXR-α and ABCA1. This heme-directed state was distinct from known macrophage states (M1, M2, Mox) and, following the same format, we have designated them Mhem.Conclusions:These results show that ATF-1 mediates HO-1 induction by heme and drives macrophage adaptation to intraplaque hemorrhage. Our definition of an ATF-1-mediated pathway for linked protection from foam cell formation and oxidant stress may have therapeutic potential.
Boyle JJ, Johns M, Lo J, et al., 2011, Heme Induces Heme Oxygenase 1 via Nrf2 Role in the Homeostatic Macrophage Response to Intraplaque Hemorrhage, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 31, Pages: 2685-U826, ISSN: 1079-5642
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- Citations: 91
Neilan M, Boyle J, Lawrie A, et al., 2011, THE ROLE OF TILRR IN VASCULAR CELL INFLAMMATION AND DEVELOPMENT OF ATHEROSCLEROSIS, HEART, Vol: 97, Pages: 6-7, ISSN: 1355-6037
Sperone A, Dryden NH, Birdsey GM, et al., 2011, The Transcription Factor Erg Inhibits Vascular Inflammation by Repressing NF-κB Activation and Proinflammatory Gene Expression in Endothelial Cells, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 31, Pages: 142-150, ISSN: 1079-5642
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- Citations: 50
Malik TH, Cortini A, Carassiti D, et al., 2010, The Alternative Pathway Is Critical for Pathogenic Complement Activation in Endotoxin- and Diet-Induced Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice, CIRCULATION, Vol: 122, Pages: 1948-U122, ISSN: 0009-7322
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- Citations: 45
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