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Vascular signalling

Group leaders

  • Dr Barbara Kemp-Harper, BSc(Hons) PhD
  • Dr Joanne Favaloro, BSc(Hons) PhD

Section Heads

  • Vascular Protein Chemistry: Dr Peter Schmidt, Diploma (Biology), PhD
  • Vascular Signal Transduction: Dr Sabine Meurer, Diploma (Chemistry) PhD
  • Vascular Biochemistry: Dr Nils Opitz, MD

Background

The Vascular Signalling research group is internationally renowned in the field of NO-sGC-cGMP signalling and free radical biology. The team is interested in vasodilator principles and their function in health and disease, with the ultimate aim of identifying new therapeutic targets in the treatment of cardiovascular disease. We utilise novel activators of sGC and employ an extensive range of molecular, cell-biological, functional and electrophysiological techniques to study NO-sGC-cGMP function.

The ubiquitous, Nobel Prize winning, signalling molecule nitric oxide (NO), plays a pivotal role in the regulation of blood vessel function, the immune system and neuronal memory function. Whilst the synthesis of NO and its effects have been well characterized, world-wide research interest shifts now to the unanswered questions, how are these effects mediated and what can go wrong in disease?

Soluble guanylyl cyclase (sGC) is the principal receptor for NO and synthesizes the second messenger cyclic GMP (cGMP). Only together do NO-cGMP form a complete signal transduction pathway. Importantly, aberrations in sGC-mediated signaling are currently emerging as fundamental events that lead to numerous pathologies such as atherosclerosis, hypertension, heart attack, stroke and erectile dysfunction.

New mechanisms, new drugs

The therapeutic importance of the NO-sGC-cGMP signalling pathway has been well recognised for many years with NO donors used to treat vascular complications, yet the development of nitrate tolerance, scavenging of NO by reactive oxygen species and oxidation of the NO receptor, sGC limits their clinical use. Excitingly, the recent development of NO-independent sGC activators, such as BAY 58-2667, which target sGC in its oxidised state offer the potential to selectively vasodilate the diseased vasculature. We are leading our research field into a new dimension, defining sGC as a previously unrecognised, long sought, endogenous sensor of the cellular redox state. sGC is a haem protein and the existence of haem-based redox sensors has been observed in various organisms. Our preliminary data support such a fundamental role now for sGC, based on the redox status of its haem iron.

We propose that evolution has designed this archaic pathway to maintain cytoprotective signalling by NO and other endogenous species (e.g. CO, HNO) and to react to changes in cellular redox state. Collectively, our work will provide a deep insight into essential biological processes and also offer new targets for the design of diagnostics and therapeutics to treat cardiovascular disorders.

Current Projects

Switching the redox state of sGC

The NO receptor, sGC has recently been shown to exist in different oxidative states (Fe2+, Fe3+ and a haem-free form) but the physiological roles and signalling mechanisms for these different forms of NOGC are unknown. Importantly, the oxidised forms of the protein (Fe3+ and haem-free) cannot be activated by NO. These distinct redox states of sGC can now be targeted by new and specific NO-independent sGC activators, to which we have exclusive access. This project aims to unravel the role of the distinct redox forms of sGC at the level of the protein, cell and intact vasculature.

A redox switch towards vascular disease

Oxidation of sGC can be induced by reactive oxygen species, which are increased in cardiovascular disease. This oxidation renders sGC unresponsive to its endogenous ligand (NO) as well as to traditional nitrovasodilator drugs. NO-independent sGC activators now offer the unprecedented opportunity to target oxidised sGC and therefore, for the first time, selectively treat the cause of vasodilator inefficiency in diseased blood vessels. This exciting project aims to determine the full potential of novel sGC activators in the vasculature damaged by cardiovascular disease.

Further unlocking the function of NOGC

NOGC is made up of α and β subunits, of which there have been four identified to date (α1, α2, β1, β2).  Thus far α1/β1 and α2/β1 forms of the enzyme have been established however the role of the β2 subunit has not been discovered.  Recently we have shown that this β2 subunit is widely expressed suggesting it has an important physiological role.  The aim for this project is be the first to determine the importance of NOGC in the α1/β2 and α2/β2 forms.

NO- the important, yet overlooked form of nitric oxide

Nitric oxide-induced vasorelaxation is largely attributed to the free radical form of nitric oxide (NO•), however, the nitroxyl anion (NO-) is also a potent endothelium-derived vasodilator. We have shown that NO--mediated vasorelaxation is pharmacologically distinct from that of NO• and have shown that NO- donors are not limited by tolerance development like the traditionally used nitrovasodilator drugs. This project investigates the potential of NO- donors as novel vasodilators in cardiovascular disease and as anti-hypertrophic agents in cardiac failure (with Dr. Rebecca Ritchie).

Staff list

  • Dr Barbara Kemp-Harper, Senior Research Officer
  • Dr Joanne Favaloro, NHMRC Peter
  • Doherty Research Fellow
  • Dr Peter Schmidt, Von Humboldt Fellow
  • Dr Nils Opitz, Research Officer
  • Dr Sabine Meurer, Research Officer
  • Ms Jennifer Irvine, PhD Student
  • Ms Ravina Ravi, PhD Student
  • Mr Jonathon Luk, BMS (Hons)Student
Vascular Signalling Group

Left to Right: Dr. Sabine Meurer, Mr. Jonathon Luk, Dr. Barbara Kemp-Harper, Dr. Nils Opitz, Dr. Joanne Favaloro, Dr. Peter Schmidt, Ms Jennifer Irvine and Ms Ravina Ravi

Collaborators

  • Dr Johannes-Peter Stasch Bayer Healthcare, Germany
  • Dr Adrian Hobbs University College, London
  • Prof Jon Fukuto UCLA, USA
  • Prof Werner Müller-Esterl University of Frankfurt, Germany
  • Dr Michael Hust Technical University Braunschweig, Germany
  • Assoc Prof Christopher Sobey Dept Pharmacology, Monash University
  • Dr Robert Widdop Dept Pharmacology, Monash University
  • Dr Rebecca Ritchie Baker Medical Research Institute, Melbourne
  • Prof Chris Triggle RMIT University, Melbourne

Funding support

  • National Health and Medical Research Council
  • Australian Research Council Von Humbolt Foundation
  • National Heart Foundation

Key publications

  1. Dumitrascu R, Weissmann N, Ghofrani HA, Dony E, Beuerlein K, Schmidt H, Stasch JP, Gnoth MJ, Seeger W, Grimminger F, Schermuly RT (2006). Activation of Soluble Guanylate Cyclase Reverses Experimental Pulmonary Hypertension and Vascular Remodeling. Circulation 113: 286-295
  2. SCHMIDT PM, ROTHKEGEL C, WUNDER F, SCHRÖDER H, STASCH JP. Residues stabilizing the heme moiety of the nitric oxide sensor soluble guanylate cyclase. Eur. J. Pharmacol. (2005) 513: 67-74.
  3. DING J, BURETTE A, NEDVETSKYPI, SCHMIDT HHHW, WEINBERG RJ (2004). Distribution of Soluble Guanylyl Cyclase in the Rat Brain. J. Comp. Neurol. 472:437-448.
  4. MELICHAR VO, KUMAR A, BEHR-ROUSSEL D, ZABEL U, UTTENTHAL LO, SMOLENSKI A, WALTER U, BECKMAN JS, LOHMANN SM, RODRIGO J, RUPIN, VERBEUREN TJ, SCHMIDT HHHW (2004).  Activity and Expression of signalling enzymes downstream of nitric oxide is decreased in hypercholesterolemia-induced atherosclerosis in rabbits. Proc. Natl. Acad. Sci. USA 101:16671-16676.
  5. SCHMIDT PM, SCHRAMM M, SCHRÖDER H, STASCH JP. Identification of residues crucially involved in the binding of the heme moiety of soluble guanylate cyclase. J. Biol. Chem. (2004) 279: 3025-3032. Title story with cover picture.
  6. SCHMIDT P, SCHRAMM M, SCHRÖDER H, STASCH JP. Receptor binding assay for nitric oxide- and heme-independent activators of soluble guanylate cyclase. Anal. Biochem. (2003) 314: 162-165.
  7. SCHMIDT P, SCHRAMM M, SCHRÖDER H, STASCH JP. Mechanisms of nitric oxide independent activation of soluble guanylyl cyclase. Eur. J. Pharmacol. (2003) 468: 167-174.
  8. SCHMIDT P, SCHRAMM M, SCHRÖDER H, STASCH JP. Preparation of heme-free soluble guanylate cyclase. Prot. Expr. Purif. (2003) 31: 42-46.
  9. Irvine, J.C., Favaloro, J.L. & Kemp-Harper, B.K.  (2003)  NO- activates soluble guanylate cyclase and Kv channels to vasodilate resistance arteries  Hypertension, 41: 1302-1307.
  10. Favaloro, J.L. & Kemp-Harper, B.K.  (2002)  Nitric oxide (NO•) and the nitroxyl anion (NO-) have differing profiles of relaxant activity in rat mesenteric artery.  Proceedings of the Australian Health and Medical Research Congress 2002, 1157.
  11. Irvine, J.C., Favaloro, J.L. & Kemp-Harper, B.K.  (2002)  The nitroxyl anion (NO-) mediates relaxation of rat small mesenteric arteries in art via the activation of soluble guanylate cyclase and voltage dependent K+ channels.  Proceedings of the Australian Health and Medical Research Congress 2002, 2013.
  12. Kemp-Harper, B.K., McPherson, G.A. & Favaloro, J.L.  (2002)  The nitroxyl anion (NO-) mediates relaxation of small resistance arteries in part via the activation of soluble guanylate cyclase (sGC) and K+ channels.  The Pharmacologist, 44 (2), Suppl 1, A214.
    13. ZABEL U, KLEINSCHNITZ C, OH P, SMOLENSKI A, NEDVETSKY P, KUGLER P, WALTER U, SCHNITZER JE, SCHMIDT HHHW (2002). Calcium-dependent membrane association sensitises soluble guanylyl cyclase to NO. Nature Cell Biol 4, 307-311 .
  13. NEDVETSKY PI, SESSA WC, SCHMIDT HHHW (2002). There's NO binding like NOS binding: protein-protein interactions in NO/cGMP signalling. Proc Natl Acad Sci USA. 99:16510-16512.
  14. STASCH JP, SCHMIDT P, ALONSO-ALIJA C, APELER H, DEMBOWSKY K, HAERTER M, HEIL M, MINUTH T, PERZBORN E, PLEIß U, SCHRAMM M, SCHRÖDER W, SCHRÖDER H, STAHL E, STEINKE W, WUNDER F. NO- and haem-independent activation of soluble guanylyl cyclase: molecular basis and cardiovascular implications of a new pharmacological principle. Br. J. Pharmacol. (2002) 136: 773-783. Title story.