Heart Failure Research Group
Project 1 - Mitochondrial L-arginine transport and its role in the pathogenesis of heart failure
Supervisors: Dr Kylie Venardos & Prof. David Kaye
kylie.venardos@bakeridi.edu.au
The failing heart is characterized metabolically by heightened oxidative stress, abnormal mitochondrial function and altered energy metabolism. Together these processes impact adversely on contractile function and contribute to the progressive nature of heart failure. Mitochondrial metabolism is known to be regulated by nitric oxide (NO), and in this context we have previously shown that myocardial L-arginine metabolism and expression of the L-arginine CAT1 transporter appears to be altered in heart failure. Whilst a mitochondrial specific isoform of nitric oxide synthase (NOS) has been demonstrated, little is known about mitochondrial L-arginine transport and its role in mitochondrial biology.
In this study we aim to characterise the biochemical properties and regulation of the mitochondrial L-arginine transporter, determine its role in mitochondrial biology and test the novel hypothesis that impaired mitochondrial L-arginine transport plays a key role in the pathogenesis of heart failure and other cardiovascular disease states. We will also examine the biochemical and physiological effects of augmented mitochondrial L-arginine transport. This project is suitable for a Honours or PhD student and can be tailored to the students interests or abilities. It will provide the opportunity for learning a range of techniques including the isolation of respiring mitochondria from healthy hearts and various disease models such as heart failure and diabetic models; cell culture; biochemical measures (western blot, L-arginine uptake, markers of oxidative/nitrosative damage); confocal microscopy; and molecular biology (cell transfection, real-time PCR).
Understanding the nature of mitochondrial L-arginine transport and its role in mitochondrial biology will provide new insights into potential therapies for heart failure and other myocardial disorders.
Project 2 - Wnt signalling pathways and myocardial ischemia-reperfusion injury
Supervisors: Dr Kylie Venardos & Prof David Kaye
kylie.venardos@bakeridi.edu.au
Coronary heart disease remains the greatest killer in the Western world, and given our ageing population, along with increasing risk factors, it is predicted to become an even more significant problem worldwide over the next 20 years. Ischemic heart disease arises when there is an imbalance between the myocardial oxygen demand and blood supply. Faulty functioning of the coronary circulation, most commonly due to fatty atherosclerotic plaques or blood clots, causes a reduction in blood flow, and subsequently ischemia and/or myocardial infarction (MI). Reperfusion (restoration of blood flow), without doubt is the most effective treatment for ischemic myocardium. However, this produces deleterious effects upon cells, and depending on the severity, may ultimately lead to cell death. The pathogenesis of ischemia-reperfusion injury is complex including endothelial dysfunction, calcium overload and heightened oxidative stress although the key driving mechanism remains uncertain. Existence of reperfusion injury has clinical implications in the recovery of cardiac function to pre-ischemic levels, particularly following invasive procedures such as the application of stents, coronary bypass surgery, coronary angioplasty, heart transplantation or following MI. These changes contribute to increased myocardial stiffness, contractile dysfunction, reduced cardiac output, diastolic dysfunction, ventricular fibrillation and left ventricular failure which are seen after MI. Eventually this can lead to ventricular dilatation, heart failure and even sudden death.
The Wnt signalling pathways have been well conserved through evolutional processes among a variety of species and play important roles in embryonic development, cellular proliferation, differentiation, migration and survival. In humans, Wnt-mediated signalling has been known to play a role in carcinogenesis however accumulating evidence now indicates Wnt signalling is also an important mediator of inflammation and recovery from injury.
In this project we will investigate the role of the Wnt signalling pathways in ischemia-reperfusion injury of the heart and determine whether manipulation of this system provides cardioprotection. This will be done in both whole hearts and at a cellular level using models of ischemia-reperfusion injury and hypoxia-reoxygenation. This project will provide the opportunity for learning a range of techniques including cell culture; langendorff perfusion of isolated hearts including functional analysis; biochemical measures (western blot, markers of cellular injury); and molecular biology (cell transfection, real-time PCR).
