A5061543063- Nitric Oxide and Endothelin Effects
- Mitochondrial Function and Pathology
- Cardiac Ischemia and Reperfusion
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Eicosanoids and Hypertension Pharmacology
- Ion Transport and Channel Regulation
- Metabolism and Genetic Disorders
- Cardiovascular Function and Risk Factors
- Electron Spin Resonance Studies
- Atherosclerosis and Cardiovascular Diseases
- Renin-Angiotensin System Studies
- Peroxisome Proliferator-Activated Receptors
- Hormonal Regulation and Hypertension
- Genomics, phytochemicals, and oxidative stress
- Immune cells in cancer
- Graphene and Nanomaterials Applications
- Hydrogen's biological and therapeutic effects
- Cancer, Hypoxia, and Metabolism
- Anesthesia and Neurotoxicity Research
- Neonatal Respiratory Health Research
- Heart Rate Variability and Autonomic Control
- Ion channel regulation and function
- Parkinson's Disease Mechanisms and Treatments
- Advanced Nanomaterials in Catalysis
- Coronary Interventions and Diagnostics
British Heart Foundation
2013-2024
University of Oxford
2015-2024
University of Surrey
2003-2024
John Radcliffe Hospital
2013-2023
Centre for Human Genetics
2007-2022
King's College London
2022
Durham University
2020
Crabtree (United States)
2009-2015
St. Jude Children's Research Hospital
2014
Weatherford College
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...
Although the accelerated atherosclerosis and premature aging of cardiovascular system in patients with metabolic syndrome have been appreciated, mechanisms their development potential therapeutic interventions remain unresolved. Our previous studies implicated advanced glycosylation end products senescence preventable a peroxynitrite scavenger, ebselen. Therefore, effect ebselen on endothelial vasculopathy model syndrome--Zucker diabetic rats (ZDF)--was investigated. Ebselen decreased...
Tetrahyrobiopterin (BH4) is a required cofactor for the synthesis of nitric oxide by endothelial nitric-oxide synthase (eNOS), and BH4 bioavailability within endothelium critical factor in regulating balance between NO superoxide production eNOS (eNOS coupling). levels are determined activity GTP cyclohydrolase I (GTPCH), rate-limiting enzyme de novo biosynthesis. However, may also be influenced oxidation, forming 7,8-dihydrobiopterin (BH2), which promotes uncoupling. Conversely,...
5,6,7,8-Tetrahydrobiopterin (BH(4)) is an essential cofactor of nitric oxide synthases (NOSs). Oxidation BH(4), in the setting diabetes and other chronic vasoinflammatory conditions, can cause insufficiency uncoupling endothelial NOS (eNOS), manifest by a switch from (NO) to superoxide production. Here we tested hypothesis that eNOS not simply consequence BH(4) insufficiency, but rather results diminished ratio vs. its catalytically incompetent oxidation product, 7,8-dihydrobiopterin...
Tetrahydrobiopterin (BH4) is a critical determinant of endothelial nitric-oxide synthase (eNOS) activity. In the absence BH4, eNOS becomes "uncoupled" and generates superoxide rather than NO. However, stoichiometry intracellular BH4/eNOS interactions not well defined, it unclear whether BH4 deficiency alone sufficient to induce uncoupling. To address these questions, we developed novel cell lines with tet-regulated expression human GTP cyclohydrolase I (GTPCH), rate-limiting enzyme in...
The endothelial nitric oxide synthase cofactor tetrahydrobiopterin (BH4) plays a pivotal role in maintaining function experimental vascular disease models and humans. Augmentation of endogenous BH4 levels by oral treatment has been proposed as potential therapeutic strategy states. We sought to determine the mechanisms relating exogenous human pharmacokinetics both plasma tissue patients with coronary artery disease.Forty-nine were randomized receive low-dose (400 mg/d) or high-dose (700...
Background— Tetrahydrobiopterin (BH 4 ) is a key regulator of endothelial nitric oxide synthase (eNOS) activity and coupling. However, the extent to which vascular and/or systemic BH levels are altered in human atherosclerosis importance bioavailability determining function oxidative stress remain unclear. We sought define relationships between plasma biopterin patients with coronary artery disease determine how affect function, eNOS coupling, superoxide production. Methods Results— Samples...
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...
Tetrahydrobiopterin (BH4) is a required cofactor for the synthesis of NO by endothelial nitric oxide synthase (eNOS), and BH4 bioavailability critical factor in regulating balance between superoxide production (eNOS coupling). Biosynthesis determined activity GTP-cyclohydrolase I (GTPCH). However, levels may also be influenced oxidation, forming 7,8-dihydrobiopterin (BH2), which promotes eNOS uncoupling. Conversely, dihydrofolate reductase (DHFR) can regenerate from BH2, but whether DHFR...
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...
Background: Cardiovascular risk in diabetes remains elevated despite glucose-lowering therapies. We hypothesized that hyperglycemia induces trained immunity macrophages, promoting persistent proatherogenic characteristics. Methods: Bone marrow–derived macrophages from control mice and with were grown physiological glucose (5 mmol/L) subjected to RNA sequencing (n=6), assay for transposase accessible chromatin immunoprecipitation (n=6) determination of hyperglycemia-induced immunity. marrow...
ABSTRACT. Zucker diabetic fat (ZDF) rats with the metabolic syndrome and hyperlipidemia develop focal segmental sclerosis. The role of oxidative nitrosative stress in nephropathy ZDF was studied. Renal histology, function, immunohistologic biochemical parameters were evaluated at 8 22 wk age lean (ZL) after chronic treatment ebselen, an antioxidant peroxinitrite scavenger. At wk, showed hyperglycemia, no proteinuria or nephropathy, but higher levels dihydrobiopterin 3-nitrotyrosine...
AimsVascular disease states are associated with endothelial dysfunction and increased production of reactive oxygen species derived from NADPH oxidases. However, it remains unclear whether a primary increase in superoxide specifically the endothelium alters initiation or progression atherosclerosis.
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...
Background and AimsOxidative stress plays a key role in the development of metabolic complications associated with obesity, including insulin resistance most common chronic liver disease worldwide, nonalcoholic fatty disease. We have recently discovered that microRNA miR-144 regulates protein levels master mediator antioxidant response, nuclear factor erythroid 2-related 2 (NRF2). On silencing, expression NRF2 target genes was significantly upregulated, suggesting controls at level both...
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))...
The redox co-factor tetrahydrobiopterin (BH4) regulates nitric oxide (NO) and reactive oxygen species (ROS) production by endothelial NOS (eNOS) is an important redox-dependent signalling molecule in the endothelium. Loss of BH4 observed cardiovascular disease (CVD) states results decreased NO increased superoxide (O2-) generation via eNOS uncoupling. Genetic mouse models augmented synthesis have shown proof concept that can alter CVD pathogenesis. However, clinical trials therapy vascular...