Yr Athro Gary F. Baxter

Member of the School's Pharmacology & Physiology research discipline.

Research interests

• Myocardial and coronary vascular biology, with a special emphasis on the pathophysiology of acute myocardial infarction
• Cellular basis of ischaemia-reperfusion injury and mechanisms of cardioprotection

For several decades, ischaemic heart disease has been a leading cause of morbidity and mortality in the industrialised nations. While in the UK and USA there are trends towards a reduction in mortality from ischaemic heart disease, the condition is predicted to become the leading cause of death worldwide    by 2030, outstripping death due to infectious or neoplastic disesases. Ischaemic heart disease therefore represents a significant and ongoing medical and scientific challenge.

Our group aims to integrate physiological, pharmacological, biochemical and molecular biological techniques to study basic aspects of cardiac biology relating to the pathophysiology and treatment of myocardial ischaemia. Understanding the principal molecular mechanisms that result in cell death during    ischaemia-reperfusion is the basis for developing rational effective therapies for the early management of acute myocardial infarction. The group works with experimental models of ischaemia-reperfusion injury including coronary artery occlusion in vivo and ex vivo. Considerable effort is now being directed    towards the paradox of reperfusion injury and the intracellular signalling mechanisms that control cellular responses to reperfusion.

The group has had a long-standing interest in the roles of autacoid factors and their associated signal transduction mechanisms as potentially tractable therapeutic targets that might modulate responses to myocardial ischaemia-reperfusion. Our recent foci of attention include cardiovascular peptides,    including bradykinin, adrenomedullin and natriuretic peptides.

Current research projects

RhoA-dependent kinase activation as an injury signal in ischaemia-reperfusion

RhoA-dependent kinase (ROCK) is a serine-threonine protein kinase which regulates a wide variety of cellular processes. In the cardiovascular system, ROCK signalling is implicated in cytoskeletal actin assembly, cardiac myocyte hypertrophy, vascular smooth muscle contraction, and smooth muscle cell    proliferation and migration. At the Royal Veterinary College, Mr Hugo Bower and Dr Shabaz Hamid showed that selective pharmacological inhibition of ROCK during ischaemia and reperfusion protected myocardium from necrosis and suggest that the deleterious effects of ROCK activation are mediated specifically    during early reperfusion. This work is now being continued by Dr Dwaine Burley, supported by a British Heart Foundation grant.

The primary aim of this project is to understand the patterns of activation and potentially injurious roles of ROCK in post-ischaemic reperfusion. Specific objectives are:

• to obtain a detailed characterisation of ROCK activation in ischaemic and reperfused myocardium and the role of reactive oxygen species in the activation of ROCK
• to investigate the ability of ROCK to inhibit PI3-kinase/Akt activation at reperfusion as an injury-promoting mechanism during reperfusion
• to explore ROCK inhibition as a mechanism of postconditioning

We hypothesise that ROCK activation during early reperfusion inhibits a key survival signal, PI3-kinase/Akt, thus promoting the development of lethal reperfusion injury. In acute myocardial infarction, the ability of myocardium to withstand ischaemia and subsequent reperfusion is dependent on the critical    balance of pro-survival and injury-promoting signals. Hopefully, these studies will furnish an understanding of the ROCK signalling pathway as a basis for the rational treatment of reperfusion injury.

Serotonin associated injury and survival signalling in myocardium: Receptor dependant and non receptor targets for cytoprotection

• Funder: British Heart Foundation
• Value: £141,823
• Duration: three years

Role of hydrogen sulphide signalling in ischaemia-reperfusion

Hydrogen sulphide (H2S) has been identified as an endogenous gaseous mediator, produced by a regulated enzyme pathway and exerting cardiovascular actions. Mr David Johansen (visiting student from the University of Tromso, Norway) demonstrated that exogenous H2S limited experimental infarct size via    a mechanism involving opening of KATP channels. Mr David Elsey is currently supported by the British Heart Foundation to undertake PhD studies to explore the potential actions of endogenous H2S produced within the heart and coronary vessels. The project is characterising the expression of H2S generating    enzymes within myocardium and the production of H2S under ischaemic and reperfusion conditions. We are also exploring the potential for exogenously-applied H2S and –SH donors to protect against ischaemia-reperfusion injury and the signal transduction mechanisms involved.

Cytoprotective regulation of intracellular calcium in myocardium by particulate and soluble guanylate cyclases

Mr Justin Bice has recently been appointed to undertake PhD studies to further examine the role of cGMP signalling in protection against ischaemia-reperfusion (work initiated by his predecessor Dr Dwaine Burley). cGMP is an intracellular second messenger derived from GTP through the action of particulate    and soluble guanylate cyclases (pGCs and sGC). pGCs are membrane-associated receptors for natriuretic peptides whereas sGC is activated physiologically by nitric oxide (NO). Our previous work has identified that elevation of intracellular cGMP via activation of pGC by B-type natriuretic peptide (BNP)    confers a marked cytoprotective effect on myocardium under the cytotoxic conditions of ischaemia-reperfusion. Preliminary evidence suggests that this protective effect of pGC is at least partially mediated through mechanisms related to sarcoplasmic reticulum ATPase activation which would promote sarcoplasmic    reticulum Ca2+ uptake and decrease cytoplasmic Ca2+ overload, likely through activation of protein kinase G. Whether activation of sGC by NO exerts similar effects on Ca2+ handling is unclear. There is increasing evidence that cGMP from pGC and sGC may be differently compartmentalised within cells and    exert different physiological actions.

The aim of this project is to characterise the effects of pGC and sGC activation on sarcoplasmic reticulum Ca2+ handling in cardiac myocytes. The general hypothesis is that activation of pGC and sGC results in the generation of differently compartmentalised cGMP pools, resulting in different patterns    of intracellular Ca2+ regulation in myocardium subjected to ischaemia-reperfusion insult. The work is being co-supervised by Dr Ken Wann (Welsh School of Pharmacy) whose laboratory provides electrophysiological expertise, and Dr Chris George (Wales Heart Research Institute) who contributes sophisticated    Ca2+ imaging techniques.

Other recent research projects

• Dr Dwaine Burley was funded by Heart Research UK to undertake his PhD investigating the role of the cGMP/PKG signalling pathway as a pro-survival (salvage) pathway in reperfusion. He showed that the protective phenomenon called "postconditioning" is mediated by activation of the cGMP/PKG pathway in      reperfusion and explored the roles of NO and natriuretic peptides as activators of this protective response. His work pointed to differences between soluble gunaylate cyclase and particulate guanylate cyclase-derived cGMP in mediating cytoproetctive responses. This work is now being continued in the      PhD studies conducted by Justin Bice.
• The laboratory has an ongoing interest in the phenomenon of ischaemic preconditioning. In collaboration with Dr Peter Ferdinandy (University of Szeged, Hungary), Dr Zoltan Giricz and Dr Aniko Gorbe were funded under the Wellcome Trust Collaborative Research Initiative to investigate the role of cGMP/PKG      signalling in mediating preconditioning and cardioprotection and its modification by hyperlipidaemia.
• Work funded by the British Heart Foundation has identified a critical role of adrenomedullin in influencing myocardial responses to ischaemia-reperfusion (Dr Shabaz Hamid). A focus has been the ability of adrenomedullin to mediate protection particularly during post-ischaemic reperfusion through recruitment      of pro-survival (salvage) kinase pathways, including NO/cGMP signalling. Some of this work was undertaken in collaboration with Dr Tienush Rassaf and colleagues at the University Hospital of Aachen
• Work undertaken in collaboration with Dr Matthias Kleinz (formerly Royal Veterinary College) assessed the cardiac actions of apelin/APJ signalling in myocardial ischaemia-reperfusion.
• Dr Yohann Rautureau (now at the Institut de Recherche Cardiovasculaire, University of Montreal, Canada) was supported by Heart Research UK to examine how natriuretic peptide/guanylate cyclase signalling influences coronary vascular cell function, including endothelial cell signalling pathways and proliferative      responses in coronary vascular smooth muscle cells.

Current research opportunities

Projects are currently available for self-funded or independently-sponsored PhD students in the field of cardiac and coronary vascular physiology/pharmacology. PhD registration fees for candidates from EU countries are currently £3100 per annum. Please contact Professor Baxter for further information.

Current research students

• Outuba Karwi

Current post doctoral research associates

• Justin S Bice BSc PhD

Recent research students, visiting students and associates

• Dwaine Burley BSc PhD (2011)
• Dmitra Andreou (Erasmus Scholar, University of Athens, 2011)
• Paolo Strazzacappa (Erasmus Scholar, University of Padova, 2009-2010)

Currently active research collaborations

• Dr William Ford (School of Pharmacy and Pharmaceutical Sciences, Cardiff University)
• Dr Chris George (Wales Heart Research Institute, Cardiff University)
• Dr Ken Wann (School of Pharmacy and Pharmaceutical Sciences, Cardiff University)
• Dr Robert C Fowkes (Royal Veterinary College)
• Professor Derek Yellon and Dr Sean Davidson (University College London)
• Professor Peter Ferdinandy (University of Szeged, Hungary)
• Dr Tienush Rassaf (University of Aachen, Germany)

Funding bodies which support our work

• British Heart Foundation
• Medical Research Council
• Heart Research UK
• Wellcome Trust