Reader in Cardiovascular Pharmacology, University of Cambridge
Director of Human Receptor Research group
Fellow of St Catharine’s College, University of Cambridge.
Nearly half of all currently used medicines target G-protein-coupled receptors (GPCRs) belonging to Class 1 or Family A, the ‘druggable genome’. The aim of our research is to understand the role of GPCRs, together with their transmitters in the human cardiovascular system and how these are altered with disease, in particular the consequences of endothelial cell dysfunction, to identify new targets for novel drugs.
The group is unusual in being able to compare responses in diseased versus normal human tissues which can be maintained in organ baths for several hours. Using tissues obtained with ethical approval and informed consent at the time of surgery, we measure responses to chemical messengers such as endothelin-1 (ET-1), novel transmitters or drugs as changes in vascular reactivity or the force of contraction of the heart. We focus on discovering the role in man of novel ‘orphan’ GPCRs, originally predicted to exist from the human genome but recently paired with their cognate transmitters. Using this approach, we have characterized GPCRs expressed in the human cardiovascular system and identified a novel vasoactive role for transmitters including chemokines, apelin, kisspeptins, and trace amines.
Chemokine receptor CCR5: from AIDS to atherosclerosis
The G-protein coupled receptor CCR5 is activated principally by endogenous inflammatory chemokines (RANTES, MIP-1α, MIP-1β). CCR5 has an essential role as a co-receptor in HIV infection that has led to development of the first selective CCR5 antagonist in clinical use. Recent evidence suggests loss of CCR5 receptor function in humans and mouse knockouts delays progression of atherosclerosis. We have discovered a new and unsuspected role for CCR5 ligands in vasoconstriction in human coronary artery and saphenous vein which can be fully blocked by CCR5 antagonists including anti-HIV drug, maraviroc. These antagonists block intimal hyperplasia in saphenous vein organ culture. Our current objective is to provide proof of principle that a new pharmacological approach using CCR5 antagonists will be beneficial in reducing vasospasm and the development of intimal hyperplasia that leads to atherosclerosis in human and mouse models.
Apelin peptides are present in vascular & cardiac endothelial cells in the human cardiovascular system & mediate three major actions. In human isolated heart, we have found apelins increased cardiac contractility and are the most potent inotropic agents yet discovered in this preparation. In human vessels, apelins mediate vasodilatation by releasing prostanoids, to appose the actions of vasoconstrictors such as ET-1. Removal of endothelium unmasks constrictor response by apelins acting directly on smooth muscle. Apelins are upregulated in atherosclerosis & localise to macrophages in the plaque. Apelin receptors are downregulated in dilated cardiomyopathy and ischaemic heart disease. In collaboration with Robert Glen, Dept of Chemistry, we have identified cyclic peptide and the first selective antagonist at the apelin receptor. These compounds are being used to delineate the role of apelins in cardiovascular disease.
Recently, we discovered a previously unsuspected role for the metastasis inhibitors and ‘molecular switch’ in puberty, the kisspeptins. They function as potent vasoconstrictors in humans, with a discrete localization of the kisspeptin receptor (previously designated as the gene product of GPR54), to atherosclerosis prone vessels.
In vertebrates, trace amines, such as tyramine, act as indirect sympathomimetics releasing tissue stored noradrenaline. Recently, p-tyramine and β-phenylethylamine (βPEA) have been shown to activate a novel G-protein coupled receptor, TA1 that is not activated by classical amines such as noradrenaline and 5-HT. In addition to the known actions of trace amines as sympathomimetics, our research provides evidence for a true transmitter role for trace amines in the human cardiovascular system and support the hypothesis that activation of the TA1 receptor may contribute in part to the hypertensive crisis that results from increased tyramine levels in, for example, patients on monoamine oxidase inhibitors.
The group has studied the role of endothelins since their discovery in 1988. We have found endothelin-1 to be the most potent constrictor of human blood vessels, with an unusual, long lasting action. Two different strategies are being pursued to prevent the detrimental vasoconstrictor actions of endothelin in disease: receptor antagonists or endothelin converting enzyme inhibitors. In animals, endothelin-induced vasoconstriction can occur by activation of either ETA, ETB or a mixture of both sub-types. We synthesised a series of novel sub-type selective radiolabelled ligand to identify which receptor mediated vasoconstriction in human vessels. We found a consistent pattern in humans, where the ETA receptors were the predominant sub-type (>80%) expressed by smooth muscle. Functional studies confirmed these results: ETA selective antagonists always fully reversed endothelin-1 induced vasoconstriction in both normal and diseased vessels. We proposed ETA selective antagonists would produce a beneficial vasodilatation, avoiding blocking ETBreceptors on non-vascular cells that we speculated would function as ‘clearing’ receptors.
Molecular imaging of cardiovascular GPCRs
We used positron emission tomography to resolve this question, devising a generic method to 18F label peptides and synthesised 18F endothelin-1. We showed clearance by ETB receptors in the lung and kidney prevents binding of ET-1 to receptors in the heart, an important mechanism to limit the detrimental effects caused by upregulated ET-1 in disease.
The image shows endothelin receptors in the rat in vivo using positron emission tomography.
Current research is focused on understanding the role of ET receptors in pulmonary arterial hypertension and portal hypertension.
BHF Programme: Imaging inflammation in atherosclerosis: An integrated multimodality approach
Inflammation is crucial to both the development and clinical complications of atherosclerosis. The aim of research in collaboration with Elizabeth Warburton, Franklin Aigbirhio, Martin Bennett, Adrian Carpenter, Tim Fryer, Jonathan Gillard and James Rudd is to define the biology of atherosclerotic plaques using positron emission tomography (PET) and magnetic resonance (MR) imaging. The image shows a cross section of a human carotid removed following surgery showing the distribution of macrophages with an atherosclerotic plaque.
Our earlier work established a new molecular imaging approach to quantifying plaque inflammation using the PET tracer [18F]-flurodeoxyglucose (FDG), now widely applied in atherosclerosis research and as an imaging biomarker in trials of anti-atherosclerosis drugs. Our recent work has demonstrated that alternative ‘next generation’ PET tracers have the potential to provide more specific information about the underlying biology of plaques. We are comparing the utility of these tracers to provide specific imaging read-outs of plaques in different inflammatory phases of the disease. We are investigating the role of both hypoxia and neovascularisation within plaques, and their relation to inflammation by means of novel, non-invasive custom-designed PET and MR imaging agents. Image shows simultaneous microPET/MR FDG imaging of atheroma in ApoE -/- mouse.
BHF 4-year PhD Studentship Programme in Cardiovascular Research
Dr Anthony Davenport is a participating investigator in theCambridge 4-year PhD Studentship Programme in Cardiovascular Research, funded by the British Heart Foundation.
This exciting programme is a new initiative to scientists in cross-disciplinary cardiovascular research, combining formal training in molecular and cellular biology, physiology of model organisms, human pharmacology physiology, genetics, genomics and population health sciences. The programme will operate with a 1+3 year structure. In the first year students will undertake three rotation projects to provide training in a broad range of scientific disciplines and techniques. In years 2-4, students will undertake a 3 year PhD project with a selected supervisor, strong encouragement being be given to the development of collaborative interdisciplinary projects.
Applications open in the autumn with a closing date in early January. Further information can be found at: http://www-cardiovascular.medschl.cam.ac.uk/phd
Wellcome Trust 4-Year Studentship PhD Programme in Metabolic and Cardiovascular Disease
The Wellcome Trust Cambridge 4-year PhD programme has close links and shares many investigators with the BHF-funded 4-year PhD programme in Cardiovascular Research. Students interested in cardiovascular research in Cambridge can apply to both programmes using a single application form. Together these programmes will support around 10 students per year.
Applications open in the autumn with a closing date in early January. Further information can be found at:http://www.mrl.ims.cam.ac.uk/phd/wellcome/
- Jones K, Maguire J,Davenport A.
Chemokine receptor CCR5: from AIDS to atherosclerosis. Br J Pharmacol 162: 1453-1469: 2011.
- Kirby HR, Maguire JJ, Colledge WH,Davenport AP.
International Union of Basic and Clinical Pharmacology. LXXVII. Kisspeptin receptor nomenclature, distribution, and function.Pharmacol Rev 62: 565-578:2010.
- Pitkin SL, Maguire JJ, Kuc RE, andDavenport AP.
Modulation of the apelin/APJ system in heart failure and atherosclerosis in man. Br J Pharmacol 160: 1785-1795:2010.
- Pitkin SL, Maguire JJ, Bonner TI, Davenport AP.
International Union of Basic and Clinical Pharmacology. LXXIV. Apelin receptor nomenclature, distribution, pharmacology, and function. Pharmacol Rev 62: 331-342;2010.
- Johnstrom P, Fryer TD, Richards HK, Maguire JJ, Clark JC, Pickard JD, Davenport AP.
Positron emission tomography of [18F]-big endothelin-1 reveals renal excretion but tissue-specific conversion to [18F]-endothelin-1 in lung and liver. Br J Pharmacol159: 812-819:2010.
- Bird JL, Izquierdo-Garcia D, Davies JR, Rudd JH, Probst KC, Figg N, Clark JC, Weissberg PL, Davenport AP,>Warburton EA.
Evaluation of translocator protein quantification as a tool for characterising macrophage burden in human carotid atherosclerosis. Atherosclerosis210: 388-391:2010.
- Davies JR, Izquierdo-Garcia D, Rudd JH, Figg N, Richards HK, Bird JL, Aigbirhio FI,Davenport AP, Weissberg PL, Fryer TD, Warburton EA.
FDG-PET can distinguish inflamed from non-inflamed plaque in an animal model of atherosclerosis. Int J Cardiovasc Imaging 26: 41-48. :2010.
- Mitchell JD, Kuc RE, Maguire JJ,Davenport AP.
Evidence for a novel vasospastic transmitter system, neuromedin U, in the equine digital circulation. Vet J 186: 106-109. :2010.
- Vachiery JL, Davenport A.
The endothelin system in pulmonary and renal vasculopathy: les liaisons dangereuses. Eur Respir Rev18: 260-271, 2009.
- Maguire JJ, Kleinz MJ, Pitkin SL, Davenport AP.
[Pyr1]apelin-13 identified as the predominant apelin isoform in the human heart: vasoactive mechanisms and inotropic action in disease.Hypertension. 2009;54:598-604.
- Mitchell JD, Maguire JJ, Davenport AP.
Emerging pharmacology and physiology of neuromedin U and the structurally related peptide neuromedin S.Br J Pharmacol. 2009;158:87-103.
- Maguire JJ, Parker WA, Foord SM, Bonner TI, Neubig RR,Davenport AP.
International Union of Pharmacology. LXXII. Recommendations for trace amine receptor nomenclature.Pharmacol Rev. 2009;61:1-8.
- Mitchell JD, Maguire JJ, Kuc RE, Davenport AP.
Expression and vasoconstrictor function of anorexigenic peptides neuromedin U-25 and S in the human cardiovascular system.Cardiovasc ResFeb 1; 81(2):353-61:2009.
- Harmar AJ, Hills RA, Rosser EM, Jones M, Buneman OP, Dunbar DR, Greenhill SD, Hale VA, Sharman JL, Bonner TI, Catterall WA,Davenport AP , Delagrange P, Dollery CT, Foord SM, Gutman GA, Laudet V, Neubig RR, Ohlstein EH, Olsen RW, Peters J, Pin JP, Ruffolo RR, Searls DB, Wright MW, Spedding. M.
IUPHAR-DB: the IUPHAR database of G protein-coupled receptors and ion channels.Nucleic Acids Res. Jan; 37(Database issue): D680-5:2009.
- Mead, EJ, Maguire, JJ, Kuc, RE and Davenport, AP.
Kisspeptins are novel potent vasoconstrictors in humans, with a discrete localization of their receptor GPR54, to atherosclerosis prone vessels.Endocrinology 148, 140-147:2007
- Singh, G, Maguire, JJ, Kuc RE, Skepper, JN, Fidock, M, andDavenport AP.
Characterization of the snake venom ligand [125I]-DNP binding to natriuretic peptide receptor-A in human artery and potent DNP mediated vasodilatation.British Journal of Pharmacology149;838-844:2006.
- Clarke MCH, Figg N, Maguire JJ,Davenport, AP, Goddard, M, Littlewood, TD , Bennett, MR.
Apoptosis of vascular smooth muscle cells is silent in normal arteries, but induces features of plaque vulnerability in atherosclerosis. Nature Medicine, 12; 1075-1080: 2006.
- Singh, G, Kuc, RE, Maguire, JJ, Fidock, M, Davenport, AP.
The novel snake venom ligand Dendroaspisnatriuretic peptide is selective for natriuretic peptide receptor-A in human heart: down-regulation of natriuretic peptide receptor-A in heart failure.Circulation Research 99;183-190:2006
- Bagnall, A, Kelland, NF, Gulliver-Sloan, F, Davenport, AP, Gray, GA, Yanagisawa, M, Webb, DJ and Kotelevtsev, YV.
Deletion of endothelial cell endothelin B receptors does not affect blood pressure or sensitivity to salt.Hypertension 48;286-293:2006.
- Gardiner, SM, March, JE, Kemp, PA, Maguire, JJ, Kuc RE,Davenport, APand Bennett T.
Regional heterogeneity in the haemodynamic responses to urotensin II infusion in relationto UT receptor localisation. British Journal of Pharmacology 147;612-621:2006.
- Kuc, RE, Maguire, JJ and Davenport, AP.
Quantification of endothelin recepor sub-types in peripheral tissues reveals downregulation of ETA receptors in ETB deficient mice.Experimental Biology and Medicine 231;741-745:2006.
- Johnström, P, Rudd, JHF, Richards, HK, Fryer, TD, Clark, JC, Weissberg, PL Pickard, JD and Davenport, AP.
Imaging endothelin ETB receptors using [18F]-BQ3020: in vitrochracterization and positron emission tomography (microPET).Experimental Biology and Medicine231;736-740:2006.
- Maguire, JJ, Wiley, KE, Kuc, RE, Stoneman, V Bennett, MR andDavenport, AP.
Endothelin-mediated vasoconstriction in early atherosclerosis is markedly increased in ApoE-/- mouse but prevented by atorvastatin.Experimental Biology and Medicine 231;806-812:2006.
- Davenport, APand Maguire, JJ.
Handbook of Experimental Pharmacology 176;295-329:2006.
- Singh, G and Davenport, AP.
Neuropeptide B and W:neurotransmitters in an emerging G-protein-coupled receptor system.British Journal of Pharmacology148;1033-1041:2006.