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Mineralocorticoid Receptor in cardiovascular disease
Summary
This research uses transgenic models to determine the role of specific cell types in the heart that are important for the development of heart disease and hypertension. These studies will facilitate the development of tissue selective antagonists for the MR in the treatment of heart disease.
Description
One of our major research goals is to provide a better understanding of cardiac failure and hypertension by studying the function of the mineralocorticoid receptor in these disorders.
Despite improvements over the last few decades, the health and economic burden of cardiovascular disease exceeds that of any other disease.
Cardiac failure affects approximately 300,000 Australians with 30,000 new cases diagnosed annually and approximately 8% of all prescriptions in general practice are for the treatment of hypertension.
The aldosterone, or mineralocorticoid receptor (MR), plays a central role in the pathophysiology of both cardiac failure and hypertension through effects on sodium balance and on the vascular system.
The role of the MR in cardiac function has been the focus of considerable recent attention, largely as a result of two landmark clinical trials demonstrating marked improvement in both quality of life and a reduction in mortality from the use of drugs that block the MR, when added to the standard treatment of cardiac failure. There is thus a compelling argument to better understand both the function and role of this receptor.
In addition to this role in cardiac failure, it is argued that as much as 10% of hypertension (high blood pressure) may be also caused by activation of this pathway. This impressive therapeutic benefit is, however, limited by the development of raised serum potassium levels in over 10% of patients. This reflects blockade of the receptor in non-cardiovascular tissues, in particular the kidney and colon.
These studies will characterise the mechanism by which the MR responds to steroids, and then influence both normal and abnormal responses in the whole organism.
This knowledge will form the basis for screening and development of novel agents for the treatment of hypertension and cardiovascular disease
Funding
National Health and Medical Research Council
National Heart Foundation of Australia
Outcomes
Demonstration that the cardiac fibrosis observed in the DOC/salt model is reversible with eplerenone treatment
Establishment of the DOC/salt model in transgenic mice
- Demonstration that the MR in immune cells plays a central role in heart disease and high blood pressure