Keith Channon MD, FRCP, FMedSci
Honorary Consultant Cardiologist & Director, NIHR Biomedical Research Centre, Oxford
- Cardiovascular Science
- Antoniades Charalambos, Bakogiannis Constantinos, Leeson Paul, Guzik Tomasz J, Zhang Mei-Hua, Tousoulis Dimitris, Antonopoulos Alexios S, Demosthenous Michael, Marinou Kyriakoula, Hale Ashley, Paschalis Andreas, Psarros Costas, Triantafyllou Costas, Bendall Jennifer, Casadei Barbara, Stefanadis Christodoulos, and Channon Keith M (2011) Rapid, direct effects of statin treatment on arterial redox state and nitric oxide bioavailability in human atherosclerosis via tetrahydrobiopterin-mediated endothelial nitric oxide synthase coupling. Circulation, 124(3):335-45.
- Antoniades Charalambos, Cunnington Colin, Antonopoulos Alexis, Neville Matt, Margaritis Marios, Demosthenous Michael, Bendall Jennifer, Hale Ashley, Cerrato Ruha, Tousoulis Dimitris, Bakogiannis Constantinos, Marinou Kyriakoula, Toutouza Marina, Vlachopoulos Charalambos, Leeson Paul, Stefanadis Christodoulos, Karpe Fredrik, and Channon Keith M (2011) Induction of vascular GTP-cyclohydrolase I and endogenous tetrahydrobiopterin synthesis protect against inflammation-induced endothelial dysfunction in human atherosclerosis. Circulation, 124(17):1860-70.
- Crabtree Mark J, Hale Ashley B, and Channon Keith M (2011) Dihydrofolate reductase protects endothelial nitric oxide synthase from uncoupling in tetrahydrobiopterin deficiency. Free Radic Biol Med, 50(11):1639-46.
- Bendall Jennifer K, Alp Nicholas J, Warrick Nicholas, Cai Shijie, Adlam David, Rockett Kirk, Yokoyama Mitsuhiro, Kawashima Seinosuke, and Channon Keith M (2005) Stoichiometric relationships between endothelial tetrahydrobiopterin, endothelial NO synthase (eNOS) activity, and eNOS coupling in vivo: insights from transgenic mice with endothelial-targeted GTP cyclohydrolase 1 and eNOS overexpression. Circ Res, 97(9):864-71.
- Alp Nicholas J, Mussa Shafi, Khoo Jeffrey, Cai Shijie, Guzik Tomasz, Jefferson Andrew, Goh Nicky, Rockett Kirk A, and Channon Keith M (2003) Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression. J Clin Invest, 112(5):725-35.
Endothelial cell signalling and vascular disease
We aim to understand how early changes in the endothelium and the 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.