Summary of laboratory research
Confocal microscopy demonstrating nuclear translocation of the protective transcription factor Nrf2 in response to celecoxib treatment.
The principal aim of Professor Mason’s scientific research is to establish a more detailed understanding of the mechanisms regulating vascular cytoprotection. The ultimate aim is to facilitate the rational design of novel therapies by which vascular endothelium can be conditioned to minimise vascular injury, EC dysfunction and subsequent atherogenesis in patients with systemic inflammatory diseases. The group currently employs in vitro and in vivo cellular and molecular biology techniques, making use of a variety of human and murine primary large and small vessel endothelial cells. An important component of this work is to determine how drugs including statins, rapamycin, cyclosporine, methotrexate and cyclo-oxygenase antagonists affect cytoprotective signalling pathways in vascular endothelial cells.
In recent years Professor Mason’s group has delineated signalling pathways regulating the expression of decay-accelerating factor and CD59, identifying them as inducible regulators of complement activation on the endothelial cell surface, which act to enhance cytoprotection against complement-mediated injury. This led to work identifying VEGF-R2, PKCα, PKCε and p38 MAPK as key components of the VEGF-induced signalling pathway for DAF regulation, and the demonstration that the immunosuppressive drugs cyclosporin A and rapamycin have differential effects on this pathway. Subsequent studies have demonstrated that PKCε acts downstream of PI-3K and forms a signalling complex with Akt, acting co-dependently to protect primary human vascular EC against apoptosis, through induction of the anti-apoptotic protein Bcl-2. A key component of this pathway is the ability of PKCε to selectively modulate NF-κB activity to favour induction of protective genes. An important component of the latter pathway is the activation of Nrf2- and AMPK-CREB-dependent signalling pathways. In 2014-2016, the group has reported therapeutic induction of AMPK-CREB-dependent pathways by methotrexate and by combination therapy with atorvastatin and rapamycin. When activated in vivo this pathway induces vasculoprotective genes and resistance to arterial injury.
The development of a model in the laboratory through which endothelial cells can be exposed to prolonged laminar or oscillatory shear stress has allowed a more physiologically relevant in vitro model to be developed. Using this approach we have demonstrated that expression of the complement regulatory protein CD59 is differentially regulated by laminar or oscillatory shear, via an ERK5 and KLF2-dependent pathway, and have confirmed these findings in vivo. This observation suggests that CD59 expression may be a contributory factor in the protection afforded by laminar shear against atherogenesis.
Heme oxygenase-1 is an important area of on-going study for the group. Catabolism of free heme by HO-1 generates CO, biliverdin and free iron, and these end-products are responsible for much of the biologic activity of HO-1, including anti-inflammatory, anti-apoptotic, and anti-oxidant effects. We have reported that induction of HO-1 by statins is differentially regulated in vascular endothelium exposed to laminar and oscillatory shear stress, proving the principle that biomechanical signalling influences endothelial responsiveness to pharmacological agents. Additional studies have shown that the anti-inflammatory drug celecoxib induces HO-1 via a COX-2-independent pathway. We have also established a link between HO-1 activity and resistance to complement-mediated injury. In this collaborative study with Miguel Soares (Gulbenkian Institute, Portugal), analysis of cardiac EC isolated from Hmox1-/- mice revealed a 60% reduction in DAF expression as compared to Hmox1+/+ EC, and Hmox1-/- cells showed enhanced sensitivity to complement. This led us to propose that modulation of complement activity through induction of DAF expression is an important component of the cytoprotective effects of HO-1 and its products. Subsequent studies published in 2016 have identified the HO-1 target genes critical for the regulation of angiogenesis.
Endothelial colony forming cells (ECFC) are an important focus of our on-going research. Owing to their bonafide endothelial phenotype, patient-derived ECFC hold significant promise as a means to investigate mechanisms of endothelial dysfunction, something that hitherto has been extremely challenging. The group is studying the impact of auto-immune systemic diseases including rheumatoid arthritis, large vessel vasculitis, SLE and anti-phospholipid syndrome on the endothelium. In conjunction with this work, and in collaboration with Professor David Carling (MRC London Institute of Medical Sciences based at Hammersmith Hospital), we are exploring changes in endothelial metabolism in response to hypoxia, with specific focus on AMPK and PKC signalling.
Plasma microvesicles are cell membrane-derived vesicles (100-1000 nm diameter) derived from erythrocytes, platelets, endothelium, neutrophils, monocytes and lymphocytes are increased in autoimmune rheumatic diseases. In addition to generating microvesicles, vascular endothelium is considered an important microvesicle target. A functional role for microvesicles is demonstrated by surface expression of receptors and bioactive molecules, and by contents including cytokines, signalling proteins, mRNAs and miRNAs. Of note, their impact on vascular endothelium may be protective or harmful. Endothelial microvesicle analysis is a current interest of the group, with projects studying their role in large vessel vasculitis and basic science studies exploring in vitro and in vivo impacts on vascular endothelial homeostasis.
Summary of clinical translational research
Professor Mason is also actively involved in clinical research, in collaboration with imaging colleagues at Hammersmith Hospital Professor Adil Al-Nahas, Dr Tara Barwick, Dr Syed Babar), Dr Ben Ariff, Dr Deepa Gopalan, Dr Niall Keenan, Dr Albert Busza and Dr Declan O’Regan; The Royal Brompton (Professor Dudley Pennell and Dr R Mohiaddin). The principal goal is to optimise clinical assessment and management of large vessel vasculitis and to understand the relationship between chronic endothelial dysfunction and accelerated atherosclerosis.
Collaborating with Professor Mauro Perretti (QMUL) and Professor Bhaskar DasGupta (Southend University Hospital) we have identified and reported a previously unknown role for neutrophils in the pathogenesis of giant cell arteritis. Further biomarker analysis has focused upon plasma microvesicles. Analysis of endothelial microvesicles in Takayasu arteritis has revealed a distinct signature featuring AnV CD144hi phenotype. Moreover, the increased numbers of AnV CD62e microvesicles is reversed in patients receiving anti-TNFα biologic therapy.
In collaboration with Prof Pennell and Dr Keenan, we have shown that in Takayasu arteritis, an integrated method of cardiovascular assessment by cardiac magnetic resonance imaging (CMR) provides good delineation of vessel wall thickening and can also demonstrate impaired endothelial function, dynamic ventricular function and myocardial scarring. In studies with Prof Camici (San Raffaele, Milan) using PET, we have shown that a significant proportion of patients with rheumatoid arthritis or SLE have evidence for coronary microvascular dysfunction which results in reduced coronary flow reserve and can be severe enough to cause myocardial ischemia despite normal epicardial coronary arteries. In addition, we have demonstrated the utility of PET imaging with PK11195 in large vessel vasculitis and reported the care required for the interpretation of FDG-PET scanning in patients with arterial grafts in collaboration with Dr Enrico Tombetti, Professor Angelo Manfredi and Dr Maria Picchio (San Raffaele). Current work is focused on the use of coronary CT angiography to assess coronary artery disease in large vessel vasculitis and the use of MR angiography for the quantitative assessment of arterial injury in large vessel vasculitis.
Professor David Carling, Imperial College, Faculty of Medicine, Institute of Clinical Sciences, Endothelial cell biology, hypoxia and metabolism., 2018
Dr Taryn Youngstein, Imperial College London, Large vessel vasculitis, 2018
Professor Amr Sawalha, University of Pittsburgh, Genetics of large vessel vasculitis, 2017
Professor Angelo Manfredi, Dr Maria Picchio and Dr Enrico Tombetti, Università Vita-Salute San Raffaele, Large vessel vasculitis, 2016
Professor Caroline Wheeler-Jones, Royal Veterinary College, London, Cyclo-oxygenase enzymes and the vascular endothelium., 2009
Professor Mauro Perretti,, William Harvey Institute, Queen Mary's University of London., Inflammation and the vascular endothelium and biomarkers for vasculitis., 2009
Dr Vijay Holla,, MD Anderson Cancer Centre, Houston, USA., Regulation of decay-accelerating factor, 2009
Prof Q Xu and Dr Lingfang Zeng,, Sir James Black Centre, King's College London., Vascular endothelial biology, 2008
Professor Dudley Pennell, Royal Brompton Hospital, London, CMR imaging in the connective tissue diseases, 2007
Dr Miguel P Soares, Instituto Gulbenkian de Ciencia, 2005
Dr A Samerel, The Cardiovascular Institute, Loyola University Chicago Stritch School of Medicine, Maywood, IL 60153, USA, 2004
Dr M Ohba, Institute of Molecular Oncology, Showa University, Tokyo, Japan, 2003
Dr M Leitges, Max-Planck-Institute for Experimental Endocrinology, Hannover, Germany
Dr N Okada, Nagoya City University School of Medicine, Japan
Dr B Bussolati, University of Torino, Italy
Paul Bacon Oration: Imaging Large Vessel Vasculitis, Indian Rheumatology Association Conference, Jawaharlal Institute of Postgraduate Medical Education and Research, 2019
Takayasu arteritis, 3rd EUVAS International Vasculitis Meeting, Cambridge, 2019
Accelerated atherosclerosis related to systemic inflammatory diseases, Vulnerable Plaque Meeting, Stresa, Italy, 2019
Current and Future Imaging in Large Vessel Vasculitis, University of Pennsylvania, Cutting Edge Vasculitis CME Programme, Philadelphia, 2019
Current and Future Imaging in Large Vessel Vasculitis, Marmara University, Istanbul, 6th Marmara Rheumatology Congress, 2019
Vascular Rheumatology: Endothelium, inflammation and imaging, British Society for Rheumatology Heberden Oration 2018, Liverpool UK, 2018
Role of imaging in diagnosis and follow up of Takayasu arteritis, First International Meeting on Vasculitis, Postgraduate Institute of Medical Education and Research, Changigarh, India, 2018
PET Scanning for diagnosis and therapy of large vessel vasculitis, Mayo Clinic, Rochester USA, Mayo Clinic, 2018
Large vessel vasculitis: an update, Royal Society of Medicine, London, UK, 2018
Large vessel vasculitis: an update, Ten Topics, London, 2017
Vascular cytoprotection, autoimmune disease and premature atherosclerosis, Southern zone Indian Rheumatology Association Conference, Hyderabad, India, 2017
Large Vessel Vasculitis: Are we making progress?, South West CTD Vasculitis Group Meeting, Musgrove Park Hospital Taunton, 2017
Takayasu arterits, Inaugural EUVAS course on vasculitis, Clare College Cambridge, 2017
Imaging large vessel vasculitis, China Heart Congress 2016, Beijing, 2016
Coronary artery disease in auto-immune rheumatic diseases, American Heart Association, Orlando Florida, 2015
Systemic Inflammation: Mechanisms underlying endothelial injury and therapeutic vascular protection, Brighton Musculoskeletal Research Centre, Brighton and Sussex Medical School, University of Sussex, 2015
Regulation and Therapeutic Manipulation of Anti-oxidant Enzymes in the Vasculature, Joint Meeting of the European-Society-for-Microcirculation (ESM) and European-Vascular-Biology-Organisation (EVBO), Pisa, Italy, 2015
Medical treatment of inflammatory aortic aneurysm, Charing Cross International Symposium, Grand Hall Olympia, 2014
Josep Font Memorial Lecture 'Novel imaging in the diagnosis of systemic vasculitis'., International Ten Topics, Barcelona, 2014
Clinical update of Takayasu arteritis, International Vasculitis Meeting, Parma, Italy, March 2013., Universita Degli Studi Di Parma, 2013
Large vessel imaging in GCA and PMR, International Symposium for Giant Cell Arteritis and Polymyalgia Rheumatica, Anglia Ruskin University, Postgraduate Medical Institute, 2012
Takayasu’s arteritis, European Society for Cardiology Annual Congress, Munich, 2012
Chronic systemic inflammation and cardiovascular disease, Milan Cardiology 2012, Instituto Scientifico, San Raffaele, Milan, 2012
Imaging in Vasculitis, Indian Rheumatology Association, Annual Congress, Christian Medical College, Vellore, 2011
Recent advances in ANCA-associated vasculitis, CME in Rheumatology, Postgraduate Institute for Medical Research, Chandigarh, India, 2011
Therapeutic manipulation of vascular signaling and cytoprotection, 6th European Meeting on Vascular Biology and Medicine, Jagellonian University, Krakow, Poland, 2011
Cytoprotective mechanisms in the vasculature – the pivotal role of heme oxygenase-1, Flemish Fund for Scientific Research Annual Meeting,, Namur University, Belgium, 2010
Imaging studies in large vessel vasculitis, 14th International Conference on Behçets Disease., QMUL, London, 2010
Bifunctional Role for VEGF-induced Haemoxygenase-1 in vivo: induction of angiogenesis and inhibition of leukocytic infiltration, British Microcirculation Society and The Microcirculatory Society Inc.First Joint Meeting, University of New Hampshire, USA, 2005
PET Imaging, Third International Conference on Giant Cell Arteritis and Polymyalgia Rheumatica, St John's College, Cambridge University, 2005
Advances in the management of large vessel vasculitis, Royal College of Physicians, London, 2005
AIMS of THERAPY IIMechanisms of vascular injury and cytoprotection, Emmanuel College Cambridge, Cambridge, 2004
Research Student Supervision
Al-Rashed,F, In vitro and in vivo molecular analysis of COX-2-dependent and independent cytoprotective pathways in vascular endothelium
Fourre,J, Relationship between protein kinase Cε and transcriptional co-regulator RIP140 in endothelial to cardiomyocyte cross-talk during vascular inflammation
Hartley,A, The design and translational testing of anti-oxidized LDL targeted nanoparticles for therapeutic delivery to atherosclerosis
Kabir,L, Investigation of PKC epsilon and AMP-activated protein kinase in endothelial cell metabolism and function
Kapasakalidi,A, Exploring autoantibody-mediated endothelial dysfunction in Takayasu Arteritis
Lang,M, The role of extracellular vesicles in the regulation of endothelial homeostasis and dysfunction during systemic inflammatory disease
Liakou,P, Understanding How Omega-3 Fatty Acids Found In Fish Oil Protect the Cardiovascular System
Thornton,C, Mechanisms of Vascular Protection in Systemic Inflammatory Disease
de Luca,A, Transcriptome-profiling in porcine arteries to identify shear-responsive regulators of endothelial apoptosis