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Professor Adrian Hobbs

Adrian

Professor of Cardiovascular Pharmacology

Centre: Translational Medicine and Therapeutics (Deputy Centre Lead)

Email: a.j.hobbs@qmul.ac.uk
Telephone: +44(0) 20 7882 5778

Profile

ORCID iD: 0000-0002-3589-7108

I completed my B.Sc. in Pharmacology, obtaining First Class Honours, at King’s College London in 1989 and remained at the same institution to undertake a Ph.D. with Dr. Alan Gibson. During my Ph.D. research I made a significant contribution to the understanding of the role of nitric oxide (NO) as a neurotransmitter in non-adrenergic, non-cholinergic (NANC) nerves, using the rodent anococcygeus as a classical model of nitrergic innervation. I was also the first to demonstrate the importance of NO-mediated NANC transmission in regulating airway smooth muscle tone.

Having completed my Ph.D. in the autumn of 1992, I took up a post-doctoral position in the laboratory of Nobel Laureate, Prof. Louis Ignarro, at the University of California, Los Angeles. My secondment to UCLA was supported by Fulbright-Hays and American Heart Association Research Fellowships. During this time, my attention turned to NO synthase itself and the biochemical mechanisms regulating enzyme activity. In particular, I focused on the bioactivity of nitroxyl (HNO) and provided the first convincing evidence that this molecule can be generated endogenously (by NO synthase). The significance of HNO to human physiology and pathophysiology is now at the very cutting edge of NO research, as it relates to host defence & cardiac function.

In the autumn of 1996, I returned to the UK to take up a post-doctoral position at the Wolfson Institute for Biomedical Research, University College London, under the mentorship of Sir Salvador Moncada. Since that time I have established my own independent research group with extensive peer reviewed support from the Wellcome Trust and British Heart Foundation; as well as securing my own personal funding, initially being awarded a Wellcome Trust Career Development Fellowship and later a Wellcome Trust Senior Fellowship. Since returning from the US, my group has focused on the guanylyl cyclase family of enzymes and the interaction between nitric oxide (NO) and natriuretic peptides in the cardiovascular system. This area of interest has taken my research into the realm of pulmonary hypertension and heart failure, and potentially new therapeutic approaches for these debilitating diseases.

More recently, I have initiated a programme of work that has culminated in the identification of C-type natriuretic peptide (CNP) as an important endothelium-derived vasoactive peptide, regulating local blood flow, systemic blood pressure, and the formation of new blood vessels (angiogenesis). In addition, my group have contributed to the appreciation of CNP as a critical cardioprotective molecule in health and disease. This avenue of research underpins an academic drug development programme aimed at designing & characterising small molecule agonists at natriuretic peptide receptor (NPR)-C.

Within the Heart Centre at the William Harvey Research Institute, as Professor of Cardiovascular Pharmacology, I aim to harness the translational potential of the environment, exploiting the exceptional links between pre-clinical and clinical research, with the goal of developing and evaluating novel treatments for cardiovascular disease stemming from my academic research findings; this will centre on ischaemic disorders (myocardial infarction, stroke) and pulmonary hypertension/heart failure.

Research

Group members
Dr. Amie Moyes; Dr. Reshma Baliga; Dr. Aisah Aubdool; Dr. Aemun Salam; Ms. Yasmin Dickinson

Summary

The focus of my research is the physiological and pathological actions and interactions of a family of homologous enzymes, the guanylyl cyclases (GC), with emphasis on the cardiovascular system. These proteins act as receptors for nitric oxide (NO) and natriuretic peptides and exert complementary cytoprotective, anti-atherosclerotic effects on the heart and vasculature. In accord, loss of these signalling pathways precipitates cardiovascular disease.

My group possesses diverse expertise and employs a multi-disciplinary, molecule-to-man approach including cell and molecular biology, biochemistry, in vitro & in vivo pharmacology (including several unique transgenic lines developed in-house and experimental models of disease), and clinical studies in healthy volunteers and patients, to investigate the significance of these enzymes in health and disease. The translational aspects of my work are highlighted by our ‘drug development’ programmes that are approaching, or currently undergoing, clinical evaluation.

My major research efforts include:

  • Pharmacological and biochemical characterization of the mechanism of NO-sensitive GC activation by NO-donor drugs, non NO-based enzyme activators, nitroxyl (HNO), and hydrogen sulphide (H2S).
  • Pharmacological assessment of the interaction between soluble and particulate isoforms of GC in the vasculature, in the context of pulmonary hypertension, heart failure and stroke; development of a novel combination therapy for pulmonary hypertension.
  • Evaluation of the (patho)physiological roles of CNP as a mammalian endothelium- and cardiac- derived cytoprotective mediator.
  • Investigation of the biological roles of natriuretic peptide receptor (NPR)-C in regulating vascular smooth muscle function, cardiac morphology & contractility, and leukocyte and platelet reactivity
  • Design & development of small molecule NPR-C agonists for the treatment of cardiovascular disease.

Key Publications

Full list of publications 

  1. Perez-Ternero, C., Aubdool, A.A., Makwana, R., Sanger, G.J., Stimson, R.H., Chan, L.F., Moyes, A.J. & Hobbs, A.J. (2022). C-type natriuretic peptide is a pivotal regulator of metabolic homeostasis. Proc. Natl. Acad. Sci. USA., 119, e2116470119.
  2. Grange, R.M.H., Preedy, M.E.J., Renukanthan, A., Dignam, J.P., Lowe, V.J., Moyes, .A.J, Pérez-Ternero, C., Aubdool, A.A., Baliga, R.S. & Hobbs, A.J. (2022). Multidrug resistance proteins preferentially regulate natriuretic peptide-driven cGMP signalling in the heart and vasculature. Br J Pharmacol., 179, 2443-2459.
  3. Dignam, J.P., Scott, T.E., Kemp-Harper, B.K. & Hobbs, A.J. (2022). Animal models of pulmonary hypertension: Getting to the heart of the problem. Br. J. Pharmacol., 179, 811-837.
  4. Moyes, A.J., Chu, S.M., Aubdool, A.A., Dukinfield, M.S., Margulies, K.B., Bedi, K.C., Hodivala-Dilke, K., Baliga, R.S. & Hobbs, A.J. (2020). C-type natriuretic peptide co-ordinates cardiac structure and function. Eur. Heart J., 41, 1006-1020.
  5. Hobbs, A.J., Moyes, A.J., Baliga, R.S., Ghedia, D., Ochiel, R., Sylvestre, Y., Dore, C.J., Chowdhury, K., Maclagan, K., Quartly, H.L., Sofat, R., Smit, A., Schreiber, B.E., Coghlan, G.J. & MacAllister, R.J. (2019). Neprilysin inhibition for pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled, proof-of-concept trial. Br. J. Pharmacol., 176, 1251-1267.
  6. Bubb, K.J., Aubdool, A.A., Moyes, A.J., Lewis, S., Drayton, J.P., Tang, O., Mehta, V., Zachary, I.C., Abraham, D.J., Tsui, J. & Hobbs, A.J. (2019). Endothelial C-type natriuretic peptide Is a critical regulator of angiogenesis and vascular remodeling. Circulation, 139, 1612-1628.
  7. Baliga, R.S., Preedy, M.E.J., Dukinfield, M.S., Chu, S.M., Aubdool, A.A., Bubb, K.J., Moyes, A.J., Tones, M.A. & Hobbs, A.J. (2018). Phosphodiesterase 2 inhibition preferentially promotes NO/guanylyl cyclase/cGMP signaling to reverse the development of heart failure. Proc. Natl. Acad. Sci. USA., 115, E7428-E7437.
  8. Bubb, K.J., Trinder, S.L., Baliga, R.S., Patel, J., Clapp, L.H., MacAllister, R.J. & Hobbs, A.J. (2014). Inhibition of phosphodiesterase 2 augments cGMP and cAMP signaling to ameliorate pulmonary hypertension. Circulation, 130, 496-507.
  9. Baliga, R.S., Milsom, A.B., Ghosh, S.M., Trinder, S.L., MacAllister, R.J., Ahluwalia, A. & Hobbs, A.J. (2012). Dietary nitrate ameliorates pulmonary hypertension: cytoprotective role for endothelial nitric oxide synthase and xanthine oxidoreductase. Circulation, 25, 2922-32.
  10. Baliga, R.S., Zhao, L., Madhani, M., Lopez-Torondel, B., Visintin, C., Selwood, D., Wilkins, M.R., MacAllister, R.J. & Hobbs, A.J. (2008). Synergy between natriuretic peptides and phosphodiesterase 5 inhibitors ameliorates pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med., 178, 861-9.
  11. Scotland, R.S., Cohen, M., Foster, P., Lovell, M., Mathur, A., Ahluwalia, A. & Hobbs, A.J. (2005). C-type natriuretic peptide (CNP) inhibits leukocyte recruitment and platelet-leukocyte interactions via suppression of P-selectin expression. Proc. Natl. Acad. Sci. USA., 102, 14452-14457.
  12. Scotland, R.S., Madhani, M., Chauhan, S.D., Moncada, S., Hobbs, A.J. & Ahluwalia, A. (2005). Investigation of vascular responses in endothelial nitric oxide synthase-cyclooxygenase-1 double-knockout mice. Circulation, 111, 796-803.
  13. Ahluwalia, A., Foster, P., Scotland, R.S., McLean, P.G., Mathur, A., Perretti, M., Moncada, S. & Hobbs, A.J. (2004). Anti-inflammatory activity of soluble guanylate cyclase: cGMP-dependent down-regulation of P-selectin expression and leukocyte recruitment. Proc. Natl. Acad. Sci. USA., 101, 1386-1391.
  14. Hobbs, A.J, Foster, P., Prescott, C., Scotland, R. & Ahluwalia, A. (2004). Natriuretic peptide receptor-C regulates coronary blood flow and prevents myocardial ischemia/reperfusion injury: novel cardioprotective role for endothelium-derived C-type natriuretic peptide. Circulation, 110, 1231-1235.
  15. Chauhan, S.D., Nilsson, H., Ahluwalia, A. & Hobbs, A.J. (2003). Release of C-type natriuretic peptide accounts for the biological activity of endothelium-derived hyperpolarizing factor. Proc. Natl. Acad. Sci. USA., 100, 1426-1431.
  16. Connelly, L., Palacios-Callender, M., Ameixa, C., Moncada, S. & Hobbs A.J. (2001). Biphasic regulation of NF-κB activity underlies the pro- and anti- inflammatory actions of nitric oxide. J. Immunol., 166, 3873-3881.
  17. Wolzt, M., MacAllister, R.J., Davis, D., Feelisch, M., Moncada, S., Vallance, P. & Hobbs, A.J. (1999). Biochemical characterization of S-nitrosohaemoglobin: mechanisms underlying synthesis, NO release, and biological activity. J. Biol. Chem., 274, 28983-28990.
  18. Hobbs, A.J., Fukuto, J.M. & Ignarro, L.J. (1994). Formation of free nitric oxide from L-arginine by nitric oxide synthase: Direct enhancement of generation by superoxide dismutase. Proc. Natl. Acad. Sci. USA., 91, 10992-10996.

Sponsors

Collaborators

Internal
Prof. A. Ahluwalia (QMUL); Dr. T. Chowdhury (QMUL)

External
L. Ignarro Nobel Laureate (UCLA); J. Fukuto (Sonoma State); G. Coghlan (Royal Free Hospital); B. Schreiber (Royal Free Hospital); J. Tsui (Royal Free Hospital); D. Abraham (Royal Free Hospital); D. Selwood (University College London); M. Wilkins (Imperial College London); Lan Zhao (Imperial College London); J. Klinger (Providence); Ralph Schermuly (University of Giessen); H. Schmidt (University of Maastricht); B. Kemp-Harper (Monash University); Kristen Bubb (Sydney University); F.-O. Levy (University of Oslo)

Teaching

  • BHF 4-year PhD scheme MRes coordinator
  • SSc tutor
  • PBL facilitator
  • BSc Pharmacology and Innovative Therapeutics lecturer

Disclosures

  • Consultant/advisory board member for Palatin Technologies Inc. Novo Nordisk and Bionevix Ltd. Research income received from Palatin Technologies Inc and Bionevix Ltd.
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