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Dr Anthony Davenport

Dr Anthony Davenport

Reader in Cardiovascular Pharmacology

Director of the Human Receptor Research group


Research Interests

Role of G-protein coupled receptors and biased signalling in the human cardiovascular system

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.

Apelins

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.

Kisspeptins

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.

Trace amines

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.

Endothelins

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.

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.

Keywords

G-protein coupled receptors ; Apelin ; Endothelin ; Trace amines ; Neuromedin-U ; Kisspeptins

Topics

  • Stroke
  • Cerebrovascular disorders

Key Publications

Cuhlmann S, Gsell W, Van der Heiden K, Habib J, Tremoleda JL, Khalil M, Turkheimer F, Meens MJ, Kwak BR, Bird J, Davenport AP, Clark J, Haskard D, Krams R, Jones H, Evans PC: In Vivo Mapping of Vascular Inflammation Using the Translocator Protein Tracer 18F-FEDAA1106. Mol Imaging. 2014;13(0):1-10.

Ooi CY, Sutcliffe MP, Davenport AP, Maguire JJ: Changes in biomechanical properties of the coronary artery wall contribute to maintained contractile responses to endothelin-1 in atherosclerosis. Life Sci. 2014 Apr 8. pii: S0024-3205(14)00381-6.

Kuc RE, Maguire JJ, Siew K, Patel S, Derksen DR, Margaret Jackson V, O'Shaughnessey KM, Davenport AP: Characterization of [¹²⁵I]GLP-1(9-36), a novel radiolabeled analog of the major metabolite of glucagon-like peptide 1 to a receptor distinct from GLP1-R and function of the peptide in murine aorta. Life Sci. 2014 May 2;102(2):134-8.

Kuc RE, Carlebur M, Maguire JJ, Yang P, Long L, Toshner M, Morrell NW, Davenport AP: Modulation of endothelin receptors in the failing right ventricle of the heart and vasculature of the lung in human pulmonary arterial hypertension. Life Sci. 2014 Feb 26. pii: S0024-3205(14)00262-8.

Alexander SP, Benson HE, Faccenda E, ... Davenport AP, ... Ye RD, Yonezawa A, Zimmermann M: The Concise Guide to PHARMACOLOGY 2013/14: overview. Br J Pharmacol. 2013 Dec;170(8):1449-58.

Maguire JJ, Jones KL, Kuc RE, Clarke MC, Bennett MR, Davenport AP: The CCR5 chemokine receptor mediates vasoconstriction and stimulates intimal hyperplasia in human vessels in vitro. Cardiovasc Res 2014, 101(3):513-21

Pawson AJ, Sharman JL, Benson HE, Faccenda E, Alexander SP, Buneman OP, Davenport AP, McGrath JC, Peters JA, Southan C, Spedding M, Yu W, Harmar AJ; NC-IUPHAR: The IUPHAR/BPS Guide to PHARMACOLOGY: an expert-driven knowledgebase of drug targets and their ligands. Nucleic Acids Res. 2014 Jan;42(Database issue):D1098-106.

Azizan EA, Poulsen H, Tuluc P, Zhou J, Clausen MV, Lieb A, Maniero C, Garg S, Bochukova EG, Zhao W, Shaikh LH, Brighton CA, Teo AE, Davenport AP, Dekkers T, Tops B, Küsters B, Ceral J, Yeo GS, Neogi SG, McFarlane I, Rosenfeld N, Marass F, Hadfield J, Margas W, Chaggar K, Solar M, Deinum J, Dolphin AC, Farooqi IS, Striessnig J, Nissen P, Brown MJ: Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat Genet. 2013 Sep;45(9):1055-60.

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, and Davenport 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 Pharmacol 159: 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. Atherosclerosis 210: 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.

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