Contact information
keith.channon@cardiov.ox.ac.uk
+44 (0)1865 572783
Dianne Stafford
channon_pa@cardiov.ox.ac.uk
Websites
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British Heart Foundation
Funder
Keith Channon
FMedSci FRCP
Field Marshal Earl Alexander Professor of Cardiovascular Medicine and Head of Department
- Associate Head of Medical Sciences Division (Clinical Research)
Nitric oxide and redox signalling in cardiovascular disease
We aim to understand how early changes in the endothelium and vascular wall are related to the initiation and development of vascular diseases, with a particular focus on nitric oxide signalling.
Diabetes, high cholesterol, smoking and high blood pressure are all associated with abnormalities in the function of the endothelium, the single-cell lining of blood vessels. Of particular significance are abnormalities in the action of nitric oxide (NO), one of several important molecules produced in the endothelium that help to maintain the health of the blood vessel wall. These abnormalities accelerate the processes that lead to vascular disease, including inflammation, thrombosis and atherosclerotic plaque formation.
Production of NO, by nitric oxide synthase enzymes, is highly regulated and depends on the co-factor tetrahydrobiopterin, which is made within endothelial cells. Once NO is produced, it interacts with molecular targets in the cell, but is rapidly inactivated by reactive oxygen species (ROS). Nitric oxide synthases can produce ROS as well as NO, the balance between the two determining the biological actions and pathological importance of these pathways.
In previous work, we have used both clinical studies and experimental models to explore the role of endothelial nitric oxide synthase and its regulation by tetrahydrobiopterin in vascular disease, in particular the inflammation associated with atherosclerotic plaque formation. We have developed transgenic models to increase tetrahydrobiopterin levels in the endothelium and other cell types, by overexpression of GTP cyclohydrolase 1 (GTPCH), the rate-limiting enzyme in its synthesis. We have also generated targeted knockouts of GTPCH, to work out how tetrahydrobiopterin is involved in normal function in the cardiovascular system elsewhere.
In studies of patients with diabetes and coronary artery disease, we have examined changes in endothelial function, and nitric oxide and tetrahydrobiopterin levels, and how these relate to the clinical features of disease. We have carried out clinical trials of treatments to increase tetrahydrobiopterin levels and improve endothelial function.
Key publications
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Tracking Monocyte Recruitment and Macrophage Accumulation in Atherosclerotic Plaque Progression Using a Novel hCD68GFP/ApoE
−/−
Reporter Mouse—Brief Report
Journal article
McNeill E. et al, (2017), Arteriosclerosis, Thrombosis, and Vascular Biology, 37, 258 - 263
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A key role for tetrahydrobiopterin-dependent endothelial NOS regulation in resistance arteries: studies in endothelial cell tetrahydrobiopterin-deficient mice
Journal article
Chuaiphichai S. et al, (2017), British Journal of Pharmacology, 174, 657 - 671
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A novel role for endothelial tetrahydrobiopterin in mitochondrial redox balance
Journal article
Bailey J. et al, (2017), Free Radical Biology and Medicine, 104, 214 - 225
Recent publications
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Clinical Pathway for Coronary Atherosclerosis in Patients Without Conventional Modifiable Risk Factors: JACC State-of-the-Art Review
Journal article
Figtree GA. et al, (2023), Journal of the American College of Cardiology, 82, 1343 - 1359
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Role of Human Epicardial Adipose Tissue–Derived miR-92a-3p in Myocardial Redox State
Journal article
Carena MC. et al, (2023), Journal of the American College of Cardiology, 82, 317 - 332
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Clinical quantitative coronary artery stenosis and coronary atherosclerosis imaging: a Consensus Statement from the Quantitative Cardiovascular Imaging Study Group.
Journal article
Mézquita AJV. et al, (2023), Nature reviews. Cardiology
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Determinants of recovery from post-COVID-19 dyspnoea: analysis of UK prospective cohorts of hospitalised COVID-19 patients and community-based controls
Journal article
Zheng B. et al, (2023), The Lancet Regional Health - Europe, 29, 100635 - 100635
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Cardiomyocyte tetrahydrobiopterin synthesis regulates fatty acid metabolism and susceptibility to ischaemia–reperfusion injury
Journal article
Chu SM. et al, (2023), Experimental Physiology