A5069345978- Nitric Oxide and Endothelin Effects
- Immune cells in cancer
- Atherosclerosis and Cardiovascular Diseases
- Chemokine receptors and signaling
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Eicosanoids and Hypertension Pharmacology
- Immune Response and Inflammation
- S100 Proteins and Annexins
- Cell Adhesion Molecules Research
- Phagocytosis and Immune Regulation
- Ion Transport and Channel Regulation
- Single-cell and spatial transcriptomics
- Lipoproteins and Cardiovascular Health
- Cardiovascular Disease and Adiposity
- Monoclonal and Polyclonal Antibodies Research
- Galectins and Cancer Biology
- Protease and Inhibitor Mechanisms
- Adipokines, Inflammation, and Metabolic Diseases
- Aortic aneurysm repair treatments
- Aortic Disease and Treatment Approaches
- Immunotherapy and Immune Responses
- Signaling Pathways in Disease
- Advanced MRI Techniques and Applications
- Hormonal Regulation and Hypertension
- Metabolism and Genetic Disorders
University of Oxford
2015-2024
Centre for Human Genetics
2013-2024
British Heart Foundation
2013-2023
John Radcliffe Hospital
2012-2022
McNeil Center for Early American Studies
2009-2016
King's College London
2007-2015
Cancer Research UK
2003-2014
University of Surrey
2014
New York Hospital Queens
2013
Cardiovascular Research Foundation
2013
Classical activation of macrophages (M(LPS+IFNγ)) elicits the expression inducible nitric oxide synthase (iNOS), generating large amounts NO and inhibiting mitochondrial respiration. Upregulation glycolysis a disrupted tricarboxylic acid (TCA) cycle underpin this switch to pro-inflammatory phenotype. We show that NOS cofactor tetrahydrobiopterin (BH4) modulates IL-1β production key aspects metabolic remodeling in activated murine via production. Using two complementary genetic models, we...
Myeloid-related protein 14 (MRP-14) and its heterodimeric partner, MRP-8, are cytosolic calcium-binding proteins, highly expressed in neutrophils monocytes. To understand the function of MRP-14, we performed targeted disruption MRP-14 gene mice. MRP-14(-/-) mice showed no obvious phenotype were fertile. MRP-8 mRNA but not is present myeloid cells these mice, suggesting that stability dependent on expression. A compensatory increase other proteins was detected lacking MRP-14. Although...
Objective— Galectin-3 (Gal-3) is a 26-kDa lectin known to regulate many aspects of inflammatory cell behavior. We assessed the hypothesis that increased levels Gal-3 contribute atherosclerotic plaque progression by enhancing monocyte chemoattraction through macrophage activation. Methods and Results— was found be upregulated in unstable regions carotid endarterectomy (CEA) specimens compared with stable from same patient (3.2-fold, P <0.05) at mRNA (n=12) (2.3-fold, <0.01) protein...
Inducible nitric oxide synthase (iNOS) is a key enzyme in the macrophage inflammatory response, which source of (NO) that potently induced response to proinflammatory stimuli. However, specific role NO production, as distinct from iNOS induction, responses remains unproven. We have generated novel mouse model with conditional deletion Gch1, encoding GTP cyclohydrolase 1 (GTPCH), an essential biosynthesis tetrahydrobiopterin (BH4) required cofactor for production. Mice floxed Gch1 allele...
Increased production of reactive oxygen species (ROS) throughout the vascular wall is a feature cardiovascular disease states, but therapeutic strategies remain limited by our incomplete understanding role and contribution specific cell ROS to pathogenesis. To investigate endothelial (EC) in development structural disease, we generated mouse model endothelium-specific Nox2 overexpression tested susceptibility aortic dissection after angiotensin II (Ang II) infusion.A increase transgenic mice...
Transcriptionally activated monocytes are recruited to the heart after acute myocardial infarction (AMI). After AMI in mice and humans, number of extracellular vesicles (EVs) increased acutely. In EV correlated closely with extent injury. We hypothesized that EVs mediate splenic monocyte mobilization program transcription following AMI. Some plasma bear endothelial cell (EC) integrins, both proinflammatory stimulation ECs significantly VCAM-1-positive release. Injected EC-EVs localized...
A major site of action for the atheroprotective drug nicotinic acid (NA) is adipose tissue, via G-protein-coupled receptor, GPR109A. Since, tissue an active secretory organ that contributes both positively and negatively to systemic inflammatory processes associated with cardiovascular disease, we hypothesized NA would act directly upon adipocytes alter expression pro-inflammatory chemokines, anti-inflammatory adipokine adiponectin.TNF-alpha treatment (1.0ng/mL) 3T3-L1 resulted in increase...
Adipose-secreted WNT5A triggers vascular disease in obesity, activating smooth muscle cell migration by an NADPH oxidase–dependent mechanism.
Abstract Chemokine signalling drives monocyte recruitment in atherosclerosis and aortic aneurysms. The mechanisms that lead to retention accumulation of macrophages the vascular wall remain unclear. Regulator G-Protein Signalling-1 (RGS1) deactivates G-protein signalling, reducing response sustained chemokine stimulation. Here we show Rgs1 is upregulated atherosclerotic plaque reduces macrophage chemotaxis desensitizes receptor signalling. In early lesions, regulates required for formation...
Apolipoprotein A1 (apoA1) is the major protein component of high-density lipoprotein (HDL) and has well documented anti-inflammatory properties. To better understand cellular molecular basis actions apoA1, we explored effect acute human apoA1 exposure on migratory capacity monocyte-derived cells in vitro vivo. Acute (20–60 min) treatment induced a substantial (50–90%) reduction macrophage chemotaxis to range chemoattractants. This was vivo as shown by pre-treatment monocytes prior adoptive...
Macrophages are mononuclear phagocytes derived from haematopoietic progenitors that widely distributed throughout the body. These cells participate in both innate and adaptive immune responses lie central to processes of inflammation, development, homeostasis. Macrophage physiology varies depending on environment which they reside exhibit rapid functional adaption response external stimuli. To study macrophages vitro, typically cultured ex vivo peritoneum or alveoli, differentiated myeloid...
AimsUnderstanding endothelial cell repopulation post-stenting and how this modulates in-stent restenosis is critical to improving arterial healing post-stenting. We used a novel murine stent model investigate post-stenting, comparing the response of drug-eluting stents with primary genetic modification improve function.
Tetrahydrobiopterin (BH4) is an essential cofactor for endothelial nitric oxide synthase (eNOS) function and NO generation. Augmentation of BH4 levels can prevent eNOS uncoupling improve dysfunction in vascular disease states. However, the physiological requirement de novo cell biosynthesis remains unclear. We generated a novel mouse model with cell-specific deletion GCH1, encoding GTP cyclohydrolase 1, enzyme biosynthesis, to test cell-autonomous vivo. Mice floxed GCH1 allele (GCH1(fl/fl))...
Significance We have recently identified the sequence of ether lipid-cleaving enzyme alkylglycerol monooxygenase. Like nitric oxide synthases and aromatic amino acid hydroxylases, monooxygenase needs tetrahydrobiopterin as cofactor. Whereas former enzymes well-established roles in cell, physiology is still not clear. Here we show its regulation murine macrophage differentiation dependence on cofactor live macrophage-like RAW264.7 cells. Upon modulation activity key biosynthesis, observe...
The CX3C chemokine fractalkine (CX3CL1) has a critical role in the development of atherogenesis because apolipoprotein-E-deficient mice lacking CX3CL1 or its receptor CX3CR1 develop smaller plaques and polymorphisms are associated with altered risk cardiovascular disease. is found on numerous cell types involved but seems to have key monocyte function. We aimed elucidate human survival determine mechanism by which spares monocytes from apoptosis.Primary were prepared healthy donors subjected...
The S100A8/A9 heterodimer is abundantly expressed by myeloid cells, especially neutrophils, but its mechanism of action only partially determined. In this study we investigated involvement in the host response to Streptococcus pneumoniae infection making use S100a9(-/-) mice that lack expression cells. were infected intranasally with pneumococci rapidly succumbed, 80% mortality after 48 h, whereas majority wild-type recovered. Over time period, displayed an average 6-fold reduction...
The cofactor tetrahydrobiopterin (BH4) is a critical regulator of endothelial NOS (eNOS) function, eNOS-derived NO and ROS signalling in vascular physiology. To determine the physiological requirement for de novo cell BH4 synthesis vasomotor function resistance arteries, we have generated mouse model with cell-specific deletion Gch1, encoding GTP cyclohydrolase 1 (GTPCH), an essential enzyme biosynthesis, evaluated BH4-dependent eNOS regulation, generation.The reactivity second-order...
GTP cyclohydrolase I catalyses the first and rate-limiting reaction in synthesis of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthases (NOS). Both eNOS iNOS have been implicated progression atherosclerosis, with opposing effects knockout mice. However, pathophysiologic requirement BH4 regulating both function, loss on atherosclerosis remains unknown.Hyperlipidemic mice deficient Gch1 endothelial cells leucocytes were generated by crossing Gch1fl/flTie2cre ApoE-/-...