Guanylate cyclase research
|Reader in Cardiovascular Pharmacology|
|Tel: +44 20 7679 7161|
Dr. Adrian Hobbs completed his B.Sc. in Pharmacology, obtaining First Class Honours, at King’s College London in 1989. Following that, Adrian remained at King’s College to undertake a Ph.D. investigating the role of nitric oxide (NO) as a neurotransmitter in non-adrenergic, non-cholinergic (NANC) nerves. After completing his Ph.D. in the autumn of 1992, Adrian took up a post-doctoral position in the laboratory of Nobel Laureate, Prof. L.J. Ignarro, at UCLA under the auspices of Fulbright-Hays and American Heart Association Fellowships. During his time in the US, Adrian focused on the biochemistry and pharmacology of NO synthase and the role of NO in host defence. At the end of 1996, Adrian returned to the UK to take up a post-doctoral position at the Wolfson Institute for Biomedical Research, UCL. Since that time, Adrian has established his own independent research group with extensive peer reviewed support from the Wellcome Trust, BHF and BBSRC; as well as securing his own personal funding in the form of Wellcome Trust Career Development and Senior Fellowships. Adrian’s group focuses on the guanylate cyclase family of enzymes and the interaction between NO and natriuretic peptides in the cardiovascular system. Adrian joined the Department of Pharmacology at UCL in September 2007 and became a Reader in Cardiovascular Pharmacology in 2008.
Adrian has been a member of the British Pharmacological Society since 1997 and served as an Editor for the British Journal of Pharmacology from 2000-2005. Adrian was awarded the British Pharmacological Society’s Novartis Prize in 2004 for his scientific contributions to pharmacology.
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. We possess diverse expertise and employ a multi-disciplinary, molecule-to-man approach including in vitro and in vivo pharmacology (including global and conditional knockout animals), biochemistry and cell and molecular biology to investigate the significance of these enzymes in health and disease. We also conduct translational research in human volunteers.
Soluble guanylate cyclase (sGC)
This heterodimeric haemoprotein catalyses the formation of the intracellular second messenger cyclic guanosine-3’,5’-monophosphate (cGMP) which in turn regulates a plethora of cellular functions via activation of specific kinases, ion channels and phosphodiesterases. The enzyme has gained notoriety as the principal receptor for the ubiquitous signalling molecule, nitric oxide (NO), forming the NO-sGC-cGMP signal transduction axis. This pathway is pivotal in the regulation of diverse physiological processes in the cardiovascular, respiratory, gastrointestinal, urogenital, nervous and immune systems. Due to its ubiquitous nature, aberrant activity of this enzyme is likely to have significant pathological implications. This is particularly true of the cardiovascular system in which dysfunction of NO-sGC-cGMP signalling is involved in diseases such as atherosclerosis, stroke and sepsis. Thus, novel drugs based on selective activators and inhibitors of the enzyme are likely to have considerable therapeutic benefit. We have a number of research interests including:
- High level expression of active recombinant human sGC; purification of expressed protein and determination of the crystal structure of the enzyme
- Pharmacological and biochemical characterisation of the mechanism of sGC activation by NO-donor drugs (eg. S-nitrosothiols, organic nitrates), non NO-based enzyme activators (eg. YC-1, BAY 41-2272), nitroxyl (HNO) and carbon monoxide (CO)
- Biochemical evaluation of enzyme regulation (eg. phosphorylation, nitration, nitrosation), with particular emphasis on redox-based control
- Pharmacological assessment of the interaction between sGC and pGC in the vasculature in vitro and in vivo
- Determination of polymorphisms in the sGC genes and potential expressional/functional consequences
- Role of the NO-sGC-cGMP pathway in regulating pro-inflammatory gene expression
Our current research interests include:
- Functional pharmacological and biochemical evaluation of the regulation of the pGC/cGMP system in vascular tissue, and interactions with sGC
- Development of a novel combination therapy for pulmonary arterial hypertension exploiting sGC/pGC interactions
- Investigation of the beneficial effects of dietary nitrate (and nitrite) in preventing cardiovascular disease
- Physiological and pathological roles of CNP as a mammalian endothelium-derived hyperpolarising factor (EDHF) in regulating vascular tone and blood flow
- Investigation of novel biological roles of the natriuretic peptide receptor type C (NPR-C) in regulating vascular smooth muscle, leukocyte and platelet reactivity
- Design and development of small molecule NPR-C agonists and antagonists for the treatment of cardiovascular disease
We have ongoing collaborations with groups within UCL (particularly Clinical Pharamcology) and other academic institutions in the UK and US. We also have industrial partners including Bayer AG (exploring the pharmacology of novel non NO-based sGC activators) and Pfizer Ltd (studies in sGC knockout mice).
Particulate guanylate cyclase (pGC)
Particulate guanylate cyclases are membrane-bound cGMP-forming enzymes that possess extracellular domains that act as receptors for the family of natriuretic peptides including atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). These peptides are released predominantly from the cardiac atria in response to volume-induced stretch and are potent relaxants of vascular smooth muscle and promote natriuresis to lower systemic blood pressure. We have demonstrated an important reciprocal regulation of cGMP-mediated responses in the vasculature between sGC and pGC and have also identified novel actions for and C-type natriuretic peptide (CNP) as an endothelium-derived regulator of vascular smooth muscle reactivity (via activation of natriuretic peptide receptor (NPR)-C).
- 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.
- Paolocci, N., Jackson, M.I., Lopez, B.E., Miranda, K., Tocchetti, C.G., Wink, D.A., Hobbs, A.J. & Fukuto, J.M. (2007). The pharmacology of nitroxyl (HNO) and its therapeutic potential: not just the Janus face of NO. Pharmacol. Ther., 113, 442-58.
- Madhani, M., Hobbs, A.J. & MacAllister, R.J. (2006). Reciprocal regulation of human soluble and particulate guanylate cyclases in vivo. Br. J. Pharmacol., 149, 797-801.
- Madhani, M., Patra, A.K., Miller, T., Eroy-Reveles, A.A., Hobbs, A.J., Fukuto, J.M. & Mascharak, P.K. (2006). Biological activity of designed photolabile metal nitrosyls: Light-dependent activation of soluble guanylate cyclase and vasorelaxant properties in rat aorta. J. Med. Chem., 49, 7325-7330. Connelly, L., Madhani, M. & Hobbs, A.J. (2005). Resistance to endotoxic shock in endothelial nitric oxide synthase (eNOS) knockout mice: a pro-inflammatory role for eNOS-derived NO in vivo. J. Biol. Chem., 280, 10040-10046.
- 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.
- 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.
- Hobbs, A., 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.
- 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.
- 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., Jacobs, A.T., Palacios-Callender, M., Moncada, S. & Hobbs, A.J. (2003). Macrophage endothelial nitric-oxide synthase autoregulates cellular activation and pro-inflammatory protein expression. J. Biol. Chem., 278, 26480-26487.
- Madhani, M., Scotland, R.S., MacAllister, R.J. & Hobbs, A.J. (2003). Vascular natriuretic peptide receptor-linked particulate guanylate cyclases are modulated by nitric oxide-cyclic GMP signalling. Br. J. Pharmacol., 139, 1289-1296.