We study how the heart meets its high and variable energy demands in order to identify novel strategies that may be beneficial in disease.
Myocardial Energetics in Ischaemia and Heart Failure
Weight for weight the heart has higher energy requirements than any other organ. Therefore maintaining energy provision is fundamental to normal cardiac function and impairment may contribute to ischaemic heart disease and chronic heart failure, both major killers worldwide.
In the search for new therapeutic approaches, we are using transgenic mouse models to modify cardiac energy metabolism. For example, within heart muscle cells, creatine kinase (CK) catalyses the reversible transfer of a high energy phosphoryl group from ATP onto creatine to form phosophocreatine (PCr). PCr is the main energy storage and transport molecule in the heart – available for very rapid regeneration of ATP during periods of ischaemia or high workload.
We have studied the importance of a fully-functioning CK system using knockout models, e.g. hearts without creatine or CK. These hearts have a reduced ability to increase their workload at times of high energy demand, and show impaired recovery following acute ischaemia and reperfusion (I/R). To perform the converse experiment we have created a creatine transporter over-expression model, which has elevated creatine and PCr in the heart. After I/R these hearts have less tissue damage and better functional recovery. This represents a novel therapeutic strategy for cardiac protection, which has potential clinical applications. Understanding the biochemical regulation of the creatine transporter is therefore a key focus of our current research alongside the identification of small molecule modulators, which we are pursuing in collaboration with AstraZeneca under their 'Open Innovation' platform. Similar approaches are being used to target aspects of CK enzyme activity.
Exploring the role for homoarginine in cardiac physiology and disease
Homoarginine (hArg) is a naturally occurring amino acid structurally similar to arginine, but with no known biochemical role. Low plasma homoarginine levels are associated with increased risk of stroke, myocardial infarction and heart failure in epidemiological studies, but the underlying biology is poorly understood. We have shown that hArg supplementation preserves contractile reserve (i.e. the ability of the heart to increase work when required) in a murine model of ischaemic heart failure. Studies are ongoing aimed at understanding the underlying mechanisms and pathways that link hArg levels to cardiac function in health and disease.
We are a multi-disciplinary group utilising a wide-range of techniques from the molecular level to whole organism. Standard biochemical and molecular biology techniques (e.g. Western blot, HPLC, protein activity assays, radiolabel uptake, PCR, immunoprecipitation), cell culture studies (e.g. confocal microscopy, hypoxia-reoxygenation, siRNA knockdown), ex vivo mitochondrial respiration and Langendorff isolated perfused heart. We have developed extensive expertise with in vivo quantification of cardiac function and structure having created state-of-the-art facilities, e.g. for conscious ECG, body composition analysis, high-frequency ultrasound (Visualsonics Vevo 3100 system), left ventricular pressure measurements (Millar pressure-volume system). These tools are routinely applied to models of LV hypertrophy, chronic heart failure and ischaemia/reperfusion injury.
Prof Angela Russell, Chemistry Research Laboratory, University of Oxford
Prof Jurgen Schneider, Institute of Cardiovascular and Metabolic Medicine, University of Leeds
Dr Dorothee Atzler, Ludwig-Maximilians-University of Munich
Dr Marko Vendelin, Tallinn University of Technology, Estonia
Prof Dirk Isbrandt, DZNE Bonn/University Hospital of Cologne