Professor of Cardiovascular Pharmacology
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 in the Pharmacology Department. 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. L.J. Ignarro, in the Department of Pharmacology at the University of California, Los Angeles. My first two years at UCLA were supported by a Fulbright-Hays Research Fellowship and subsequently I was awarded a Fellowship by the American Heart Association to remain in Prof. Ignarro’s lab for a further two years. 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.
At the end 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, BHF and BBSRC; 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 guanylate cyclase family of enzymes and the interaction between NO and natriuretic peptides in the cardiovascular system. This area of interest has taken my research into the realm of pulmonary hypertension and potentially new therapeutic approaches for this debilitating disease (schematic).
More recently, I have initiated a programme of work that has culminated in the identification of C-type natriuretic peptide as an important endothelium-derived vasoactive peptide; in addition, I have discovered and characterised a novel signalling pathway in the blood vessel wall, triggered by CNP, involving activation of natriuretic peptide receptor-C (NPR-C) and G-protein gated inwardly-rectifying K+ channels (GIRKs) that regulating vascular tone, local blood flow and systemic blood pressure (schematic).
Within the Heart Centre at the WHRI, 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.
Summary of Research
The focus of our research is the physiological and pathological actions and interactions of a family of homologous enzymes, the guanylate 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 transgenics and 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 sGC activation by NO-donor drugs, non NO-based enzyme activators, nitroxyl (HNO), carbon monoxide (CO) 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-derived hyperpolarising factor (EDHF) in regulating vascular tone and blood flow
- Investigation of the biological roles of the natriuretic peptide receptor (NPR)-C in regulating vascular smooth muscle, leukocyte and platelet reactivity; design & development of small molecule NPR-C agonists for the treatment of cardiovascular disease.
For a full list of publist publications click here
(* Denotes equal contribution and # corresponding author)
Moyes, A.J., Khambata, R.S., Villar, I., Bubb, K.J., Baliga, R.S., Lumsden, N.G., Xiao, F., Gane, P.J., Rebstock, A.S., Worthington, R.J., Simone, M.I., Mota, F., Rivilla, F., Vallejo, S., Peiró, C., Sánchez Ferrer, C.F., Djordjevic, S., Caulfield, M.J., MacAllister, R.J., Selwood, D.L., Ahluwalia, A. & Hobbs, A.J.# (2014). Endothelial C-type natriuretic peptide maintains vascular homeostasis. J. Clin. Invest., 124, 4039-51.
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.
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.
Villar, I.C., Scotland, R.S., Khambata, R.S., Chan, M., Duchene, J., Sampaio, A.L., Perretti, M., Ahluwalia, A.*# & Hobbs, A.J.* (2011). Suppression of endothelial P-selectin expression contributes to reduced cell trafficking in females: an effect independent of NO and prostacyclin. Arterioscler Thromb Vasc Biol., 31, 1075-83.
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.
Marro, M.L., Peiró, C., Panayiotou, C.M., Baliga, R.S., Meurer, S., Schmidt, H.H. & Hobbs, A.J.# (2008). Characterization of the human alpha1 beta1 soluble guanylyl cyclase promoter: key role for NF-kappaB(p50) and CCAAT-binding factors in regulating expression of the nitric oxide receptor. J. Biol. Chem., 283, 20027-36.
Villar, I.C., Panayiotou, C.M., Sheraz, A., Madhani, M., Scotland, R.S., Nobles, M., Kemp-Harper, B., Ahluwalia, A. & Hobbs, A.J.# (2007). Definitive role for natriuretic peptide receptor-C in mediating the vasorelaxant activity of C-type natriuretic peptide and endothelium-derived hyperpolarising factor. Cardiovasc. Res., 74, 515-525.
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.
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.
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.
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.
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