Gillian cockerill

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...

Proteomics is evolving as an important research technique in cardiovascular disease. We present exploratory research for a systemic biomarker of abdominal aortic aneurysm (AAA) in serum. Forty patients, 20 with large AAAs and 20 matched controls, were prospectively recruited. Serum was harvested, enriched, and mined for differential protein expression. Difference in gel electrophoresis using a two-dimensional platform, cyanine labeling, and Progenesis SameSpots software identified protein spots with significantly altered intensity...

OBJECTIVE: Abdominal aortic aneurysm (AAA) development is associated with increased angiogenesis and overexpression of vascular endothelial growth factor (VEGF). Inhibition of angiogenesis results in attenuation of experimental aneurysms. This study investigated the effects of recombinant human (rh)VEGF on experimental aneurysms. METHODS: Apolipoprotein E-deficient (apoE(-/-)) mice were assigned to one of four groups: (1) normal saline infusion (sham), (2) angiotensin-II (AngII) infusion, (3) AngII infusion plus 100 microg daily rhVEGF for 14 days (AngII+14dVEGF), or (4) AngII infusion plus 100 microg daily rhVEGF for 21 days (AngII+21dVEGF)...

RATIONALE: Histone deacetylase (HDAC)7 is expressed in the early stages of embryonic development and may play a role in endothelial function. OBJECTIVE: This study aimed to investigate the role of HDAC7 in endothelial cell (EC) proliferation and growth and the underlying mechanism. METHODS AND RESULTS: Overexpression of HDAC7 by adenoviral gene transfer suppressed human umbilical vein endothelial cell (HUVEC) proliferation by preventing nuclear translocation of beta-catenin and downregulation of T-cell factor-1/Id2 (inhibitor of DNA binding 2) and cyclin D1, leading to G(1) phase elongation...

Selumetinib (AZD6244, ARRY-142886) is a selective, non-ATP-competitive inhibitor of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-1/2. The range of antitumor activity seen preclinically and in patients highlights the importance of identifying determinants of response to this drug. In large tumor cell panels of diverse lineage, we show that MEK inhibitor response does not have an absolute correlation with mutational or phospho-protein markers of BRAF/MEK, RAS, or phosphoinositide 3-kinase (PI3K) activity...

BACKGROUND: Histone deacetylase 3 (HDAC3) is known to play a crucial role in the differentiation of endothelial progenitors. The role of HDAC3 in mature endothelial cells, however, is not well understood. Here, we investigated the function of HDAC3 in preserving endothelial integrity in areas of disturbed blood flow, ie, bifurcation areas prone to atherosclerosis development. METHODS AND RESULTS: En face staining of aortas from apolipoprotein E-knockout mice revealed increased expression of HDAC3, specifically in these branching areas in vivo, whereas rapid upregulation of HDAC3 protein was observed in endothelial cells exposed to disturbed flow in vitro...

BACKGROUND: Development and rupture of aortic aneurysms involve a combination of complex biological processes. Rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, has been shown to have a broad spectrum of effects in vivo. The hypothesis that rosiglitazone would reduce aneurysm expansion or rupture was tested in the angiotensin II (Ang II)-induced hypercholesterolemic mouse model. METHODS AND RESULTS: Apolipoprotein E-deficient mice, 12 months of age, were allocated to 4 groups...

INTRODUCTION: Arterial diseases including atherosclerosis, intimal hyperplasia and aneurysms have been shown to be a product of genotype and environment. Gene expression pathways rely on protein translation to generate target effects. As a result of alternative splicing and post-translational modifications, one gene does not code for a single protein but for many. Proteomic studies allow quantification of these proteins in a biological system and determination of altered protein expression in disease...

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X-box binding protein 1 (XBP1) is a key signal transducer in endoplasmic reticulum stress response, and its potential role in the atherosclerosis development is unknown. This study aims to explore the impact of XBP1 on maintaining endothelial integrity related to atherosclerosis and to delineate the underlying mechanism. We found that XBP1 was highly expressed at branch points and areas of atherosclerotic lesions in the arteries of ApoE(-/-) mice, which was related to the severity of lesion development. In vitro study using human umbilical vein endothelial cells (HUVECs) indicated that disturbed flow increased the activation of XBP1 expression and splicing...

AIMS: Matrix metalloproteinase (MMP) activity is central to the development of left ventricular (LV) remodelling and dysfunction after acute myocardial infarction (AMI). We assessed the relationships with LV structure and function and outcome, of tissue inhibitors of metalloproteinase-1 (TIMP-1) and MMP-9, and compared with N-terminal pro-B-type natriuretic peptide (NTproBNP). METHODS AND RESULTS: We studied 404 patients with AMI. Primary outcome measures were the associations of TIMP-1, MMP-9, and NTproBNP with death or heart failure, and with LV dimensions, function and remodelling (ΔLVEDV, change in LV end-diastolic volume between discharge and follow-up)...

AIM: To describe temporal profiles of plasma matrix metalloproteinases (MMP-2 and MMP-9), and their relationship with echocardiographic (Echo) parameters of left ventricular (LV) function and remodelling, after acute myocardial infarction (AMI) in man. METHODS AND RESULTS: Plasma MMP-2 and MMP-9 were assayed at intervals (0-12, 12-24, 24-48, 48-72, 72-96, and > 96 h) in 91 patients with AMI (ST-elevation/non-ST-elevation 77/24; 73% male; 40% anterior site) and on a single occasion in 172 age- and sex-matched control subjects with stable coronary artery disease...

OBJECTIVE: Circulating plasma interleukin-6 (IL-6) concentrations are elevated in patients with abdominal aortic aneurysms (AAAs) compared with controls. In vitro studies suggest that the aneurysm is the source of the IL-6. Because IL-6 is an independent risk factor for cardiovascular mortality, elevation of this cytokine may be significant in these patients, who represent a group at increased risk from cardiovascular death. The aim of this study was to directly measure in vivo aortic IL-6 concentrations, testing the hypothesis that aneurysms secrete IL-6 into the circulation...

Endothelial progenitor cells (EPCs) are a population of circulating stem cells that hone in to sites of vascular injury where they undergo differentiation to become incorporated into damaged tissue. The aim of this study was to enumerate EPCs in patients with abdominal aortic aneurysms (AAA). CD133(+) peripheral blood mononuclear cells were immunomagnetically selected and CD34/CD133 was used as a marker of EPCs. EPCs were detected using flow cytometry. AAA patients had significantly higher levels of circulating EPCs than age-matched controls (2...

Studies suggest that aneurysm-derived cytokines perpetuate the cycle of inflammation and proteolysis that is the pathological hallmark of abdominal aortic aneurysms (AAA). As interleukin (IL)-6 is an independent risk factor for cardiovascular mortality, such cytokines may also have important systemic effects. The purpose of this study was to investigate the effect of aneurysm repair on circulating levels of cytokines. Inflammatory cytokines were measured in 99 patients with AAA and 100 patients who had undergone AAA repair in the past...

In keeping with the inflammatory paradigm of abdominal aortic aneurysm (AAA) pathophysiology, in vitro studies suggest that aneurysms secrete the proinflammatory cytokine interleukin-6 (IL-6). Circulating IL-6 levels are higher in patients with AAA with elevated circulating IL-6 an independent risk factor for cardiovascular mortality. To investigate whether aneurysms secrete IL-6 into the circulation, arterial IL-6 was measured from within the aorta in three groups of patients undergoing endovascular procedures; 27 AAA, 10 thoracic aneurysms (TA), and 15 controls...

Abdominal aortic aneurysm (AAA) rupture is associated with elevated levels of matrix metalloproteinase (MMP). Medial neovascularization is a known characteristic of established AAAs and involves proteolytic degradation of extracellular matrix by MMPs to facilitate endothelial cell proliferation and migration. This study evaluated the extent of neovascularization in abdominal aortic aneurysm rupture. Results indicated upregulation of proangiogenic cytokines and increased medial neovascularization at the aneurysm rupture edge compared with paired aneurysm anterior sac...

To search for novel transcriptional pathways that are activated in abdominal aortic aneurysm rupture, cDNA microarrays were used to compare global mRNA expression at the aneurysm rupture edge to anterior sac, and selected results were confirmed using quantitative real-time-polymerase chain reaction (QRT-PCR). This study identified apoptosis, angiogenesis, and inflammation as potentially important participants during the process of aneurysm rupture.

The mechanisms of hypoxia-mediated aneurysm wall weakening and rupture are unknown. During hypoxia, strategies to maintain cellular ATP levels include increasing glycolysis (glycolytic strategy) or decreasing ATP consumption (metabolic depression). This study demonstrated that compared to anterior aneurysm sac, rupture edge overexpressed hypoxia-inducible factor-1-alpha (marker of hypoxia) and showed no significant difference in levels of combined ADP and ATP or lactate (glycolytic end product). Further studies are needed to confirm whether hypoxic AAA cells adapt through metabolic depression rather than glycolysis...

The pathogenesis of abdominal aortic aneurysm (AAAs) involves progressive cycles of proteolysis and inflammation, the product of proteolysis driving subsequent inflammation. Little is yet known about the initiating events. We review the specific literature examining the possibility that MMP-2 may be the initial catalyst. Histologically, elastolysis is one of the earliest observable events in aneurysm genesis. Matrix metalloproteinase-2 (MMP-2), as the dominant gelatinase differentially expressed in aneurysmal tissue and cells derived from aneurysms, would be a good candidate...