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), Arterioscler Thromb Vasc Biol, 37, 258 - 263
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A Key Role for Tetrahydrobiopterin-Dependent Endothelial NOS Regulation in Vascular Resistance Arteries: Studies in Endothelial Cell Tetrahydrobiopterin-Deficient Mice
Journal article
Chuaiphichai S. et al, (2017), British Journal of Pharmacology
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A Novel Role for Endothelial Tetrahydrobiopterin in Mitochondrial Redox Balance
Journal article
Bailey JD. et al, (2017), Free Radical Biology and Medicine
Recent publications
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Comparison of a Fully Angiography-Derived Versus a Hybrid of Angiography and Pressure-Wire-Derived Approach to Assess Coronary Microvascular Resistance: The Oxford Acute Myocardial Infarction Hybrid (OxAMI-HYBRID) Study.
Journal article
Chai J. et al, (2024), Catheter Cardiovasc Interv
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Association between kidney function, frailty and receipt of invasive management after acute coronary syndrome.
Journal article
Scott JK. et al, (2024), Open Heart, 11
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Emerging opportunities to target inflammation: myocardial infarction and type 2 diabetes.
Journal article
Kufazvinei TTJ. et al, (2024), Cardiovasc Res, 120, 1241 - 1252
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Mast cell-derived BH4 and serotonin are critical mediators of postoperative pain.
Journal article
Starkl P. et al, (2024), Sci Immunol, 9
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Mutagenesis on a complex mouse genetic background by site-specific nucleases.
Journal article
Davies B. et al, (2024), Transgenic Res