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https://www.readbyqxmd.com/read/27899403/meta-analysis-of-genome-wide-association-studies-for-abdominal-aortic-aneurysm-identifies-four-new-disease-specific-risk-loci
#1
Gregory T Jones, Gerard Tromp, Helena Kuivaniemi, Solveig Gretarsdottir, Annette F Baas, Betti Giusti, Ewa Strauss, Femke N van 't Hof, Thomas Webb, Robert Erdman, Marylyn D Ritchie, James R Elmore, Anurag Verma, Sarah Pendergrass, Iftikhar J Kullo, Zi Ye, Peggy L Peissig, Omri Gottesman, Shefali S Verma, Jennifer Malinowski, Laura J Rasmussen-Torvik, Kenneth Borthwick, Diane T Smelser, David R Crosslin, Mariza de Andrade, Evan J Ryer, Catherine A McCarty, Erwin P Bottinger, Jennifer A Pacheco, Dana C Crawford, David S Carrell, Glenn S Gerhard, David P Franklin, David J Carey, Victoria L Phillips, Michael J Williams, Wenhua Wei, Ross Blair, Andrew A Hill, Thodur M Vasudevan, David R Lewis, Ian A Thomson, Jo Krysa, Geraldine B Hill, Justin Roake, Tony R Merriman, Grzegorz Oszkinis, Silvia Galora, Claudia Saracini, Rosanna Abbate, Raffaele Pulli, Carlo Pratesi, Athanasios Saratzis, Anna Verissimo, Suzannah J Bumpstead, Stephen A Badger, Rachel E Clough, Gillian W Cockerill, Hany Hafez, D J Scott, T S Futers, Simon P Romaine, Katherine Bridge, Kathryn J Griffin, Marc A Bailey, Alberto Smith, Matt M Thompson, Frank van Bockxmeer, Stefan E Matthiasson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Jan D Blankensteijn, Joep A Teijink, Cisca Wijmenga, Jacqueline de Graaf, Lambertus A Kiemeney, Jes S Lindholt, Anne E Hughes, Declan T Bradley, Kathleen Stirrups, Jonathan Golledge, Paul E Norman, Janet T Powell, Steve E Humphries, Stephen E Hamby, Alison H Goodall, Christopher P Nelson, Natzi Sakalihasan, Audrey Courtois, Robert E Ferrell, Per Eriksson, Lasse Folkersen, Anders Franco-Cereceda, John D Eicher, Andrew D Johnson, Christer Betsholtz, Arno Ruusalepp, Oscar Franzén, Eric Schadt, Johan L Björkegren, Leonard Lipovich, Anne M Drolet, Eric Verhoeven, Clark J Zeebregts, Robert H Geelkerken, Marc R van Sambeek, Steven M van Sterkenburg, Jean-Paul P de Vries, Kari Stefansson, John R Thompson, Paul I de Bakker, Panos Deloukas, Robert D Sayers, Seamus Harrison, Andre M van Rij, Nilesh J Samani, Matthew J Bown
RATIONALE: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. OBJECTIVE: To identify additional AAA risk loci using data from all available genome-wide association studies (GWAS). METHODS AND RESULTS: Through a meta-analysis of 6 GWAS datasets and a validation study totalling 10,204 cases and 107,766 controls we identified 4 new AAA risk loci: 1q32...
November 29, 2016: Circulation Research
https://www.readbyqxmd.com/read/27338006/xbp1-splicing-triggers-mir-150-transfer-from-smooth-muscle-cells-to-endothelial-cells-via-extracellular-vesicles
#2
Yue Zhao, Yi Li, Peiyi Luo, Yingtang Gao, Junyao Yang, Ka-Hou Lao, Gang Wang, Gillian Cockerill, Yanhua Hu, Qingbo Xu, Tong Li, Lingfang Zeng
The interaction between endothelial cells (ECs) and smooth muscle cells (SMCs) plays a critical role in the maintenance of vessel wall homeostasis. The X-box binding protein 1 (XBP1) plays an important role in EC and SMC cellular functions. However, whether XBP1 is involved in EC-SMC interaction remains unclear. In this study, In vivo experiments with hindlimb ischemia models revealed that XBP1 deficiency in SMCs significantly attenuated angiogenesis in ischemic tissues, therefore retarded the foot blood perfusion recovery...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27175366/increased-expression-of-lamin-a-c-correlate-with-regions-of-high-wall-stress-in-abdominal-aortic-aneurysms
#3
Amir Malkawi, Grisha Pirianov, Evelyn Torsney, Ian Chetter, Natzi Sakalihasan, Ian M Loftus, Ian Nordon, Christopher Huggins, Nicoletta Charolidi, Matt Thompson, Xie Yun Xu, Gillian W Cockerill
BACKGROUND: Since aortic diameter is the most -significant risk factor for rupture, we sought to identify stress-dependent changes in gene expression to illuminate novel molecular processes in aneurysm rupture. MATERIALS AND METHODS: We constructed finite element maps of abdominal computerized tomography scans (CTs) of seven abdominal aortic aneurysm (AAA) patients to map wall stress. Paired biopsies from high- and low-stress areas were collected at surgery using vascular landmarks as coordinates...
October 2015: Aorta (Stamford, Conn.)
https://www.readbyqxmd.com/read/26318106/a-novel-small-molecule-tlr4-antagonist-iaxo-102-negatively-regulates-non-hematopoietic-toll-like-receptor-4-signalling-and-inhibits-aortic-aneurysms-development
#4
Christopher Huggins, Stuart Pearce, Francesco Peri, Frank Neumann, Gillian Cockerill, Grisha Pirianov
OBJECTIVES: The toll-like receptors (TLRs), including TLR4, have been shown to play a crucial role in vascular inflammatory diseases, such as atherosclerosis and aneurysm. The main goal of this study was to determine the potential of IAXO-102 (Innaxon, Tewkesbury), a novel small molecule TLR4 antagonist, to modulate non-hematopoietic TLR4 proinflammatory signalling and inhibit experimental abdominal aortic aneurysm (AAA) development. METHODS: Human umbilical vein endothelial cells (HUVEC) and Angiotensin II-induced experimental AAA development were our in vitro and in vivo models respectively...
October 2015: Atherosclerosis
https://www.readbyqxmd.com/read/26140943/investigating-the-effect-of-a-single-infusion-of-reconstituted-high-density-lipoprotein-in-patients-with-symptomatic-carotid-plaques
#5
RANDOMIZED CONTROLLED TRIAL
Hosaam Nasr, Evelyn Torsney, Robin N Poston, Lawrence Hayes, David C Gaze, Russell Basser, Matthew M Thompson, Ian M Loftus, Gillian W Cockerill
BACKGROUND: Elevation of plasma high-density lipoprotein (HDL) cholesterol concentration reduces cardiovascular mortality and morbidity. HDLs have been shown to possess acute anti-inflammatory, antioxidant, and antithrombotic properties. We hypothesize that HDL therapy can acutely alter local and systemic manifestations of plaque instability. METHODS: Forty patients with early symptomatic carotid disease were randomized to either receive reconstituted HDL (rHDL) 40 mg/kg (n = 20) or placebo (n = 20)...
October 2015: Annals of Vascular Surgery
https://www.readbyqxmd.com/read/26113112/pioglitazone-identifies-a-new-target-for-aneurysm-treatment-role-of-egr1-in-an-experimental-murine-model-of-aortic-aneurysm
#6
Nicoletta Charolidi, Grisha Pirianov, Evelyn Torsney, Stuart Pearce, Ken Laing, Axel Nohturfft, Gillian W Cockerill
Peroxisome proliferator-activated receptor x03B3; agonists have been shown to inhibit angiotensin II (AngII)-induced experimental abdominal aortic aneurysms. Macrophage infiltration to the vascular wall is an early event in this pathology, and therefore we explored the effects of the peroxisome proliferator-activated receptor x03B3; agonist pioglitazone on AngII-treated macrophages. Using microarray-based expression profiling of phorbol ester-stimulated THP-1 cells, we found that a number of aneurysm-related gene changes effected by AngII were modulated following the addition of pioglitazone...
2015: Journal of Vascular Research
https://www.readbyqxmd.com/read/24046328/a-variant-in-ldlr-is-associated-with-abdominal-aortic-aneurysm
#7
Declan T Bradley, Anne E Hughes, Stephen A Badger, Gregory T Jones, Seamus C Harrison, Benjamin J Wright, Suzannah Bumpstead, Annette F Baas, Sólveig Grétarsdóttir, Kevin Burnand, Anne H Child, Rachel E Clough, Gillian Cockerill, Hany Hafez, D Julian A Scott, Robert A S Ariëns, Anne Johnson, Soroush Sohrabi, Alberto Smith, Matthew M Thompson, Frank M van Bockxmeer, Matthew Waltham, Stefán E Matthíasson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Jan D Blankensteijn, Joep A W Teijink, Cisca Wijmenga, Jacqueline de Graaf, Lambertus A Kiemeney, John B Wild, Sarah Edkins, Rhian Gwilliam, Sarah E Hunt, Simon Potter, Jes S Lindholt, Jonathan Golledge, Paul E Norman, Andre van Rij, Janet T Powell, Per Eriksson, Kári Stefánsson, John R Thompson, Steve E Humphries, Robert D Sayers, Panos Deloukas, Nilesh J Samani, Matthew J Bown
BACKGROUND: Abdominal aortic aneurysm (AAA) is a common cardiovascular disease among older people and demonstrates significant heritability. In contrast to similar complex diseases, relatively few genetic associations with AAA have been confirmed. We reanalyzed our genome-wide study and carried through to replication suggestive discovery associations at a lower level of significance. METHODS AND RESULTS: A genome-wide association study was conducted using 1830 cases from the United Kingdom, New Zealand, and Australia with infrarenal aorta diameter≥30 mm or ruptured AAA and 5435 unscreened controls from the 1958 Birth Cohort and National Blood Service cohort from the Wellcome Trust Case Control Consortium...
October 2013: Circulation. Cardiovascular Genetics
https://www.readbyqxmd.com/read/24045946/histone-deacetylase-3-unconventional-splicing-mediates-endothelial-to-mesenchymal-transition-through-transforming-growth-factor-%C3%AE-2
#8
Lingfang Zeng, Gang Wang, Dario Ummarino, Andriana Margariti, Qihe Xu, Qingzhong Xiao, Wen Wang, Zhongyi Zhang, Xiaoke Yin, Manuel Mayr, Gillian Cockerill, Julie Yi-shuan Li, Shu Chien, Yanhua Hu, Qingbo Xu
Histone deacetylase 3 (HDAC3) plays a critical role in the maintenance of endothelial integrity and other physiological processes. In this study, we demonstrated that HDAC3 undergoes unconventional splicing during stem cell differentiation. Four different splicing variants have been identified, designated as HD3α, -β, -γ, and -δ, respectively. HD3α was confirmed in stem cell differentiation by specific antibody against the sequences from intron 12. Immunofluorescence staining indicated that the HD3α isoform co-localized with CD31-positive or α-smooth muscle actin-positive cells at different developmental stages of mouse embryos...
November 1, 2013: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/23570277/increasing-access-to-chronic-disease-self-management-programs-in-rural-and-remote-communities-using-telehealth
#9
COMPARATIVE STUDY
Susan B Jaglal, Vinita A Haroun, Nancy M Salbach, Gillian Hawker, Jennifer Voth, Wendy Lou, Pia Kontos, James E Cameron, Rhonda Cockerill, Tarik Bereket
OBJECTIVE: This study examined whether a telehealth chronic disease self-management program (CDSMP) would lead to improvements in self-efficacy, health behaviors, and health status for chronically ill adults living in Northern Ontario, Canada. Two telehealth models were used: (1) single site, groups formed by participants at one telehealth site; and (2) multi-site, participants linked from multiple sites to form one telehealth group, as a strategy to increase access to the intervention for individuals living in rural and remote communities...
June 2013: Telemedicine Journal and E-health: the Official Journal of the American Telemedicine Association
https://www.readbyqxmd.com/read/23529610/vascular-endothelial-cell-growth-activated-xbp1-splicing-in-endothelial-cells-is-crucial-for-angiogenesis
#10
Lingfang Zeng, Qingzhong Xiao, Mei Chen, Andriana Margariti, Daniel Martin, Aleksandar Ivetic, Heping Xu, Justin Mason, Wen Wang, Gillian Cockerill, Kazutoshi Mori, Julie Yi-shuan Li, Shu Chien, Yanhua Hu, Qingbo Xu
BACKGROUND: Vascular endothelial cell growth factor plays a pivotal role in angiogenesis via regulating endothelial cell proliferation. The X-box binding protein 1 (XBP1) is believed to be a signal transducer in the endoplasmic reticulum stress response. It is unknown whether there is crosstalk between vascular endothelial cell growth factor signaling and XBP1 pathway. METHODS AND RESULTS: We found that vascular endothelial cell growth factor induced the kinase insert domain receptor internalization and interaction through C-terminal domain with the unspliced XBP1 and the inositol requiring enzyme 1 α in the endoplasmic reticulum, leading to inositol requiring enzyme 1 α phosphorylation and XBP1 mRNA splicing, which was abolished by siRNA-mediated knockdown of kinase insert domain receptor...
April 23, 2013: Circulation
https://www.readbyqxmd.com/read/23184933/xbp1-mrna-splicing-triggers-an-autophagic-response-in-endothelial-cells-through-beclin-1-transcriptional-activation
#11
Andriana Margariti, Hongling Li, Ting Chen, Daniel Martin, Gema Vizcay-Barrena, Saydul Alam, Eirini Karamariti, Qingzhong Xiao, Anna Zampetaki, Zhongyi Zhang, Wen Wang, Zhixin Jiang, Chan Gao, Benyu Ma, Ye-Guang Chen, Gillian Cockerill, Yanhua Hu, Qingbo Xu, Lingfang Zeng
Sustained activation of X-box-binding protein 1 (XBP1) results in endothelial cell (EC) apoptosis and atherosclerosis development. The present study provides evidence that XBP1 mRNA splicing triggered an autophagic response in ECs by inducing autophagic vesicle formation and markers of autophagy BECLIN-1 and microtubule-associated protein 1 light chain 3β (LC3-βII). Endostatin activated autophagic gene expression through XBP1 mRNA splicing in an inositol-requiring enzyme 1α (IRE1α)-dependent manner. Knockdown of XBP1 or IRE1α by shRNA in ECs ablated endostatin-induced autophagosome formation...
January 11, 2013: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/23023368/elevation-of-plasma-high-density-lipoproteins-inhibits-development-of-experimental-abdominal-aortic-aneurysms
#12
Evelyn Torsney, Grisha Pirianov, Nicoletta Charolidi, Azza Shoreim, David Gaze, Slaveia Petrova, Ken Laing, Trevor Meisinger, Wanfen Xiong, B Timothy Baxter, Gillian W Cockerill
OBJECTIVE: Patients with abdominal aortic aneurysms have lower concentrations of high-density lipoproteins (HDLs), leading us to investigate whether increasing plasma HDLs could influence aneurysm formation. METHODS AND RESULTS: Using the angiotensin II-induced hypercholesterolemic and the CaCl(2)-induced normocholesterolemic mouse model of AAA, we investigated the hypothesis that elevation of HDLs inhibits AAA. HDLs elevated before or at the time of AAA induction reduced AAA formation in both models but had no effect on early ruptures...
November 2012: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/22999334/rosiglitazone-negatively-regulates-c-jun-n-terminal-kinase-and-toll-like-receptor-4%C3%A2-proinflammatory-signalling-during-initiation-of-experimental-aortic-aneurysms
#13
Grisha Pirianov, Evelyn Torsney, Franklyn Howe, Gillian W Cockerill
OBJECTIVE: Development and rupture of aortic aneurysms (AA) is a complex process involving inflammation, cell death, tissue and matrix remodelling. The thiazolidinediones (TZDs) including Rosiglitazone (RGZ) are a family of drugs which act as agonists of the nuclear peroxisome proliferator-activated receptors and have a broad spectrum of effects on a number of biological processes in the cardiovascular system. In our previous study we have demonstrated that RGZ has a marked effect on both aneurysm rupture and development, however, the precise mechanism of this is unknown...
November 2012: Atherosclerosis
https://www.readbyqxmd.com/read/22724482/diabetes-as-a-negative-risk-factor-for-abdominal-aortic-aneurysm-does-the-disease-aetiology-or-the-treatment-provide-the-mechanism-of-protection
#14
REVIEW
Evelyn Torsney, Grisha Pirianov, Gillian W Cockerill
There is strong epidemiological evidence that patients with diabetes have a lower incidence of abdominal aortic aneurysm. The precise mechanism of this negative association is unknown. Whilst a number of studies have supported the hypothesis that protection is a function of diabetes-mediated changes in the vascular extracellular matrix biology, there is also support for the idea that the treatment regimens used in diabetes may afford protection against AAA. In particular the pleiotropic drug family, the thiazolidinediones have been examined as candidates to ameliorate aneurysm formation...
May 2013: Current Vascular Pharmacology
https://www.readbyqxmd.com/read/22436499/effects-on-lung-function-in-patients-undergoing-coronary-artery-surgery-on-versus-off-cardiopulmonary-bypass-a-randomized-trial
#15
Gunaratnam Niranjann, George Asimakopoulos, Brendan Madden, Gillian Cockerill, Matthew Thompson, Venkatachalam Chandrasekaran
BACKGROUND: : Coronary revascularization is associated with respiratory dysfunction and poor gas exchange postoperatively. Cardiopulmonary bypass (CPB) has been implicated as a possible explanation for this phenomenon. This study investigated respiratory function in patients undergoing coronary artery bypass grafting (CABG) on-CPB versus off-CPB to determine whether the off-CPB condition results in improved postoperative pulmonary function. METHODS: : Forty patients were randomized into 1 of 2 groups: CABG on-CPB (group A) or off-CPB (group B)...
2005: Innovations: Technology and Techniques in Cardiothoracic and Vascular Surgery
https://www.readbyqxmd.com/read/22055160/abdominal-aortic-aneurysm-is-associated-with-a-variant-in-low-density-lipoprotein-receptor-related-protein-1
#16
Matthew J Bown, Gregory T Jones, Seamus C Harrison, Benjamin J Wright, Suzannah Bumpstead, Annette F Baas, Solveig Gretarsdottir, Stephen A Badger, Declan T Bradley, Kevin Burnand, Anne H Child, Rachel E Clough, Gillian Cockerill, Hany Hafez, D Julian A Scott, Simon Futers, Anne Johnson, Soroush Sohrabi, Alberto Smith, Matthew M Thompson, Frank M van Bockxmeer, Matthew Waltham, Stefan E Matthiasson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Jan D Blankensteijn, Joep A W Teijink, Cisca Wijmenga, Jacqueline de Graaf, Lambertus A Kiemeney, Themistocles L Assimes, Ruth McPherson, Lasse Folkersen, Anders Franco-Cereceda, Jutta Palmen, Andrew J Smith, Nicolas Sylvius, John B Wild, Mette Refstrup, Sarah Edkins, Rhian Gwilliam, Sarah E Hunt, Simon Potter, Jes S Lindholt, Ruth Frikke-Schmidt, Anne Tybjærg-Hansen, Anne E Hughes, Jonathan Golledge, Paul E Norman, Andre van Rij, Janet T Powell, Per Eriksson, Kari Stefansson, John R Thompson, Steve E Humphries, Robert D Sayers, Panos Deloukas, Nilesh J Samani
Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0...
November 11, 2011: American Journal of Human Genetics
https://www.readbyqxmd.com/read/22027828/galectin-9-protein-expression-in-endothelial-cells-is-positively-regulated-by-histone-deacetylase-3
#17
Saydul Alam, Hongling Li, Andriana Margariti, Daniel Martin, Anna Zampetaki, Ouassila Habi, Gillian Cockerill, Yanhua Hu, Qingbo Xu, Lingfang Zeng
Galectin-9 expression in endothelial cells can be induced in response to inflammation. However, the mechanism of its expression remains unclear. In this study, we found that interferon-γ (IFN-γ) induced galectin-9 expression in human endothelial cells in a time-dependent manner, which coincided with the activation of histone deacetylase (HDAC). When endothelial cells were treated with the HDAC3 inhibitor, apicidin, or shRNA-HDAC3 knockdown, IFN-γ-induced galectin-9 expression was abolished. Overexpression of HDAC3 induced the interaction between phosphoinositol 3-kinase (PI3K) and IFN response factor 3 (IRF3), leading to IRF3 phosphorylation, nuclear translocation, and galectin-9 expression...
December 23, 2011: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/21747056/downregulation-of-kv7-4-channel-activity-in-primary-and-secondary-hypertension
#18
Thomas A Jepps, Preet S Chadha, Alison J Davis, Maksym I Harhun, Gillian W Cockerill, Søren P Olesen, Rie S Hansen, Iain A Greenwood
BACKGROUND: Voltage-gated potassium (K(+)) channels encoded by KCNQ genes (Kv7 channels) have been identified in various rodent and human blood vessels as key regulators of vascular tone; however, nothing is known about the functional impact of these channels in vascular disease. We ascertained the effect of 3 structurally different activators of Kv7.2 through Kv7.5 channels (BMS-204352, S-1, and retigabine) on blood vessels from normotensive and hypertensive animals. METHODS AND RESULTS: Precontracted thoracic aorta and mesenteric artery segments from normotensive rats were relaxed by all 3 Kv7 activators, with potencies of BMS-204352=S-1>retigabine...
August 2, 2011: Circulation
https://www.readbyqxmd.com/read/21741794/comparative-proteomics-reveals-a-systemic-vulnerability-in-the-vasculature-of-patients-with-abdominal-aortic-aneurysms
#19
Ian M Nordon, Robert J Hinchliffe, Amir H Malkawi, Grisha Pirianov, Evelyn Torsney, Ian M Loftus, Gillian W Cockerill, Matt M Thompson
INTRODUCTION: Abdominal aortic aneurysms (AAA) are associated with inflammation, apoptosis, and matrix degradation. AAA tissue represents the end stage of disease, limiting its utility in identification of factors culpable for initiation of aneurysm development. Recent evidence suggests that AAAs are a local representation of a systemic disease of the vasculature. Morphologic and molecular changes, comparable to those found in the aneurysm wall, have been demonstrated in veins from patients with AAAs...
October 2011: Journal of Vascular Surgery
https://www.readbyqxmd.com/read/21037321/novel-aspects-of-the-pathogenesis-of-aneurysms-of-the-abdominal-aorta-in-humans
#20
REVIEW
Jean-Baptiste Michel, José-Luis Martin-Ventura, Jesus Egido, Natzi Sakalihasan, Vladislav Treska, Jes Lindholt, Eric Allaire, Unnur Thorsteinsdottir, Gillian Cockerill, Jesper Swedenborg
Aneurysm of the abdominal aorta (AAA) is a particular, specifically localized form of atherothrombosis, providing a unique human model of this disease. The pathogenesis of AAA is characterized by a breakdown of the extracellular matrix due to an excessive proteolytic activity, leading to potential arterial wall rupture. The roles of matrix metalloproteinases and plasmin generation in progression of AAA have been demonstrated both in animal models and in clinical studies. In the present review, we highlight recent studies addressing the role of the haemoglobin-rich, intraluminal thrombus and the adventitial response in the development of human AAA...
April 1, 2011: Cardiovascular Research
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