Heart Failure Pharmacology
Project 1 - Targeting reactive oxygen species (ROS)-induced damage in the DIABETIC HEART: A role for PHOSPHOINOSITIDE 3-KINASE P110α (PI3kα)?
Supervisors: Dr Rebecca Ritchie, Dr Julie McMullen, Dr Marissa Bowden
More than one million Australians currently have diabetes, and the disorder is the sixth leading cause of death in our nation, mostly due to cardiovascular disease. Diabetes is closely linked to coronary artery disease and hypertension, however, a specific cardiomyopathy, independent of these cardiovascular risks, often develops in diabetic patients. Human diabetic cardiac disease is particularly characterised by early diastolic dysfunction and late systolic impairment. Such impairments may be accompanied with an increased susceptibility to post-ischaemic myocardial damage. Our laboratories have also shown impaired glucose handling in diabetic mice results in cardiomyocyte (heart muscle cells) enlargement (hypertrophy). Consequently, this form of cardiomyopathy is a major contributor to high morbidity and mortality in diabetic patients.
In Australia, treatment of the cardiac complications in diabetic patients is still not being adequately achieved, and new interventions specifically for managing these cardiac complications of diabetes are essential. Recent studies by Dr Ritchie have shown increased levels of toxic chemicals called reactive oxygen species (ROS) in diabetic heart tissues. ROS is normally removed by naturally-occurring antioxidants in the body, however, diabetic patients have lower amounts of antioxidants both in their hearts and in their blood. The elevated levels of ROS in the diabetic heart, along with general decreased antioxidant function, plays a pivotal role in impairing the pumping and the remodelling of the diabetic heart.
Activation of the p110a isoform of phosphoinositide 3-kinase (PI3Kα) has been shown by Dr. McMullen to protect the heart in several cardiac pathologies.
Together, Dr Ritchie and Dr McMullen have recently shown that antioxidants may enhance the activity of this protective PI3Kα pathway to improve cardiac function in the diabetic heart. In addition, deficits in PI3Kα may actually increase ROS in the heart. Therefore, we propose that PI3Kα regulates ROS production, and that by increasing its activity in the diabetic heart, the damage caused by ROS can be overcome.
The aim of this current project is to investigate whether increased activity of PI3Kα signalling protects against diabetes-induced cardiac dysfunction in vivo. Furthermore, to determine how this increase in PI3Kα compares to antioxidant therapy. The cell size of the cardiomyocytes in the diabetic heart will also be investigated. Depending on whether the successful applicant is seeking an Honours or PhD project, the scope of this project will use transgenic approaches in mice with type 1 diabetes, and will provide the opportunity for learning a range of techniques, including in vitro techniques (using cardiomyocytes), and ex vivo (isolated mouse hearts). In addition, assessment of myocardial function, histochemical, biochemical (Western blot analyses, thin layer chromatography, ROS detection), molecular (real time PCR), physiological and pharmacological techniques. As a PhD project, it would also incorporate a mouse model of type 2 diabetes, and/or in vitro techniques (diabetic cardiomyocytes), and ex vivo (isolated diabetic mouse hearts) studies. This project can be tailored according to the student's abilities and interests.
It is likely that stronger antioxidant approaches and/or drugs that activate protective protein pathways, such as PI3Kα, alone or on top of current therapy, will be more effective in treating and thereby reversing, the impaired function and preventing or delaying heart failure, in the diabetic heart.
Project 2 - Novel Activators of soluble GUANYLATE CYCLASE as new treatments for cardiac hypertrophy
Supervisors: Dr Rebecca Ritchie, Dr Barbara Kemp-Harper & Dr Jennifer Irvine
Cardiac hypertrophy, or enlargement of the heart, develops in response to high blood pressure, and is a contributing factor to congestive heart failure. Development of cardiac hypertrophy is thought to result from increased production of oxygen-derived free radicals such as superoxide and activation of growth signals such as mitogen-activated protein kinases (MAPK) and calcineurin. We have previously shown the NO·/sGC/cGMP signalling system to act as a powerful cardiac antihypertrophic mechanism.
Nitroxyl (HNO) is a novel redox sibling of NO· which may have therapeutic advantages over NO· in the treatment of various cardiovascular diseases. We have recently shown that HNO prevents hypertrophy in isolated cardiomyocytes (heart muscle cells). Moreover, HNO prevents excess generation of superoxide. Yet, its mechanism of action beyond this step has not been elucidated. In addition, we have access to two direct and NO·-independent activators of sGC. These compounds are also resistant to superoxide scavenging and their impact upon the hypertrophic response (including activity of pro-hypertrophic signalling, hypertrophic gene expression) is not yet determined.
This project aims to assess the mechanisms via which HNO mediates its antihypertrophic action under both physiological and pathophysiological conditions, such as diabetes, and to compare its effects to that of the NO donor, DEA/NO and the NO-independent activators of sGC. Depending on whether the successful applicant is seeking an Honours or PhD project, the scope of this project can include in vitro techniques (using cardiomyocytes and/or cardiac fibroblasts), and ex vivo (Langendorff-perfused isolated rat hearts from diabetic vs non-diabetic animals) models of cardiac hypertrophy. As a PhD project, it would also incorporate in vivo models of cardiac hypertrophy, such as mice subjected to transverse aortic constriction (TAC). This project can be tailored according to the student's abilities and interests and will provide the opportunity for learning a range of techniques, including cell culture, biochemical (Western blot analyses), molecular (real time PCR), physiological and pharmacological techniques.
This study will elucidate the therapeutic potential of HNO and sGC ligands to provide innovative pharmacotherapy for the treatment of heart failure and other cardiovascular diseases.
We are also offering a Student Summer Scholarship project 2009/2010 which may be of interest to students contemplating an Honours degree in the future.
Contact
Rebecca.Ritchie@bakeridi.edu.au
Heart Failure Pharmacology
Baker IDI Heart and Diabetes Institute
8532 1392
Jennifer.Irvine@bakeridi.edu.au
Heart Failure Pharmacology
Baker IDI Heart and Diabetes Institute
8532 1238
