Professor Ajay Shah MD FRCP FMedSci
BHF Professor of Cardiology
James Black Professor of Medicine
Head of Cardiovascular Division &
Honorary Consultant Cardiologist
King’s College London
The James Black Centre
125 Coldharbour Lane
London SE5 9NU
Executive Assistant - Monica Brennan
Tel: +44 (0)20 7848 5189
Professor Ajay Shah graduated from the University of Wales College of Medicine in 1982. His postgraduate doctoral training was undertaken with Dirk Brutsaert in Belgium and Andrew Henderson in Cardiff, his thesis being awarded with Distinction in 1990. Subsequent academic training included a British Heart Foundation Intermediate Fellowship, a period at the National Institutes of Health in the USA, and a Medical Research Council Senior Clinical Fellowship. He was appointed to the Chair of Cardiology at King's College London in 1998. The title of James Black Professor of Medicine was conferred on him in 2014.
He is an elected Fellow of the Academy of Medical Sciences, the European Society of Cardiology, the American Heart Association, and the International Academy of Cardiovascular Sciences, and a member of the Association of Physicians of Great Britain and Ireland. He is the current Chairman of the European Society of Cardiology Working Group on Myocardial Function and the Chairman of the Basic Science section of the Heart Failure Association of the European Society of Cardiology (2006- ). He is on the editorial board of Heart , European Heart Journal , Cardiovascular Research, Journal of Molecular & Cellular Cardiology, European Journal of Heart Failure, Basic Research in Cardiology , Heart Lung & Circulation, and Heart & Vessels. He has also led the establishment of the annual Winter Congress on Translational Basic Science of the Heart Failure Association of the ESC.
The group is based within the new £30M James Black Centre at the Denmark Hill campus of King’s College London. We study the role of NADPH oxidases and redox-regulated pathways involved in the development of cardiac hypertrophy, failure and vascular dysfunction. We employ an integrative multidisciplinary approach to address this focused area, with molecular, cellular, biochemical, physiological and clinical techniques and a strong emphasis on carefully phenotyped relevant gene-modified models, several of which have been generated within the group. With respect to translational research and clinical application, we are well integrated with the clinical cardiac unit at King’s College Hospital and have established access to patients, clinical material and excellent clinical research facilities. Our work is funded through British Heart Foundation programme and project grants, EU grants and a range of other awards.
The main current areas of research are:
(a) NADPH oxidases in cardiac hypertrophy, remodelling and heart failure
The mechanisms underlying the development of cardiac hypertrophy in response to increased workload or of adverse remodelling post-MI, and the subsequent transition to heart failure, remain incompletely understood. Our work focuses on the role of reactive oxygen species (ROS, such as superoxide and hydrogen peroxide) and redox-regulated pathways in this process. Although there are several potential sources of ROS in the heart, we have focussed specifically on the NADPH oxidase family of enzymes as these proteins appear to be specifically designed for redox signalling. NADPH oxidases are complex multi-subunit enzymes in which a Nox catalytic subunit facilitates the transfer of electrons from NADPH to molecular oxygen, thereby resulting in the formation of superoxide and then hydrogen peroxide. Of the 5 Nox isoforms identified to date, Nox2 and Nox4 are co-expressed in endothelial cells, cardiomyocytes and fibroblasts. ROS production by NADPH oxidases may be stimulated in an isoform-specific manner by agonists such as angiotensin II and other G-protein coupled receptor agonists, growth factors, cytokines and mechanical stimuli. Our previous work includes the first definitive evidence for the presence of NADPH oxidases in cardiomyocytes and endothelial cells, as well as significant contributions to defining its mechanisms of regulation and role in redox signalling in these cells. We discovered that Nox2 is involved in both experimental and human heart failure and found that it has a pivotal role in signalling angiotensin II- and aldosterone-induced hypertrophy and fibrosis. Subsequently, we found that not only are Nox2 and 4 differentially activated in cardiac hypertrophy but that they modulate distinct components of the overall cardiac hypertrophic response, suggesting that these different facets may be amenable to independent regulation.
Increased expression of NADPH oxidease subunits in failing human heart (left) compared to non-failing (right)
Our key objectives now are to: (a) define the distinct Nox2- and Nox4-activated pathways that influence specific facets of the cardiac and vascular responses to chronic overload (eg, hypertrophy, fibrosis, contractile dysfunction), so that detrimental pathways might be specifically targetted; (b) investigate the molecular and cellular mechanisms of Nox4 versus Nox2 activation and coupling to downstream signalling pathways; (c) elucidate molecular mechanisms responsible for the transcriptional regulation of the Noxs; and (d) investigate the involvement of Noxs in human cardiovascular disease.
(b) NADPH oxidases and endothelial dysfunction
Endothelial dysfunction is a key early event in atherogenesis and a powerful predictor of future cardiovascular morbidity and mortality. A major factor in the development of endothelial dysfunction is redox imbalance involving excess ROS production which leads not only to the inactivation of nitric oxide (NO) but also modulates the activity of redox-sensitive intracellular signalling pathways. We and others have shown that a Nox2-based NADPH oxidase is a major source of endothelial ROS but that endothelial cells also express Nox4. In studies complementary to those addressing the role of Noxs in cardiac hypertrophy and remodelling, we are also addressing the relative roles of Nox2 and Nox4 in endothelial cells both in vitro and in vivo. The relative roles of Nox-derived ROS and NOS-derived NO are also of interest.
Confocal image showing colocalisation of the NADPH oxidase subunit gp91phox and tubulin in endothelial cells
(c) Autocrine/paracrine regulation of contractile function
A long-standing interest has been in the cardiac contractile actions of locally-released mediators such as NO, both in the physiological setting and in heart failure. This question has been addressed with a wide range of techniques and models, ranging from sarcomere length and intracellular calcium measurements in isolated cardiomyocytes to invasive cardiac catheterisation laboratory-based studies in humans. More recently, we have focussed on the role of the myofilament protein troponin I in these effects, using among other models the transgenic replacement of cardiac troponin I by slow skeletal troponin I. Our current work is addressing the effects of ROS and NO on contractile function both experimentally and in humans in vivo.
Pressure-volume analysis of human LV function
BHF Specialist Fellow
Dr N Anilkumar
Dr M Hancock
Dr C Harrison
Dr H Mongue-Din
Dr C Santos
Dr I Smyrnias
Visiting Research Associates
Specialist support staff
Ms L Beltran (Lab manager)
Dr A Protti
Dr G Sawyer (p/t)
Dr X Zhang (p/t)
Dr X Dong
Mr I Sawyer
Ms A Emmerson
Dr A Nabeebaccus (MRC Clinical Training Fellow)
Dr H Shabeeh (BHF Clinical PhD Fellow)