Cardiovascular Endocrinology Research Group
Research Group Head
The Cardiovascular Endocrinology group’s research provides critical insights into how the mineralocorticoid receptor (MR) controls fibrosis and inflammation in the heart muscle, immune cells (macrophages) and the blood vessel wall (endothelial cells).
Their findings have identified mechanisms for MR signalling in promoting the onset and development of heart disease, particularly in the development of cardiac tissue fibrosis and inflammatory responses. The group’s recently published data from transgenic animals has identified important novel functions of the MR in individual cell types in the heart including macrophages, heart muscle cells, and endothelial cells of the blood vessel wall. They are now working to determine the molecular pathways in each cell type in which MR plays a role to understand how this occurs, and how silencing these pathways may provide new options for the treatment of heart failure.
Cardiac-selective MR antagonists would provide the excellent cardiac protection of current antagonists but avoid side effects. The Cardiovascular Endocrinology group’s research program focuses on identifying tissue-specific MR signalling mechanisms to understand how hormones such as aldosterone (a mineralocorticoid) and cortisol (a glucocorticoid) can regulate the MR in tissues where salt and water regulation is not involved. The new knowledge gained is essential for development of cardiac-selective MR antagonists.
Dr Young and her team have also identified novel protein interactions within the MR that are unique for each of the hormones that bind the receptor. Understanding of the properties of these novel proteins and their regulation at a cellular level, offers further options for the development of therapeutics for heart disease.
Together, these studies have produced data that supports earlier clinical studies showing that MR antagonists are equally effective in patients without high levels of the mineralocorticoid hormone aldosterone. The group has shown that in these circumstances, disease is due to activation of the MR by the closely related hormone, cortisol.
This research will enable development of targeted drugs that act specifically on the heart, protecting patients from heart failure and disease without side effects associated with the blockade of MR in other areas of the body such as the kidney.
- Mineralocorticoid receptor in cardiovascular disease
- Identification of ligand-selective MR antagonists
Rickard, A.J., Morgan, J., Tesch, G., Funder, J.W., Fuller, P.J., and M.J. Young (2009). Deletion of mineralocorticoid receptors from macrophages protects against DOC/salt-induced cardiac fibrosis and hypertension. Hypertension. 54(3):537-43. CI=53 IF=6.8.
Editorial: M.J. Young (Chief Guest Editor) Fuller PJ, Stowasser M, Mihailidou AS. (2013) Frontiers in Science Review Series. Aldosterone and salt; heart and kidney. A symposium of the 24th International Society of Hypertension, 2012. Clinical and Experimental Pharmacology and Physiology. 40(12):872–875
Rickard, AJ, Morgan, J., Bienvenu, LA., Fletcher, EK., Cranston, GA, Shen, JZ., Reichelt, ME., Delbridge, L.M. and MJ. Young. (2012). Cardiomyocyte MR signaling is essential for DOC/salt-mediated cardiac fibrosis and blood pressure regulation. Hypertension. 60:1443-50
Bienvenu, LA., Morgan J., Tesch, G.H., Cranston, G.A., Fletcher, EK., Delbridge, LM, MJ. Young. (2012). Macrophage mineralocorticoid receptor signaling plays a key role in aldosterone-independent cardiac fibrosis. Endocrinology. 153(7):3416-25.
Armani, A., Cinti, F., Marzolla, V., Morgan, J., Cranston,G.A.,Antelmi, A., Carpinelli, G., Canese, R., Pagotto, U., Quarta, C.,Malorni, W., Matarrese, P., Marconi, M., Fabbri, A., Rosano, G., Cinti, S., Young, M.J.* and M. Caprio*. Mineralocorticoid Receptor antagonism counters metabolic dysfunctions induced by high fat diet in mice, through browning of the adipose organ. FASEB accepted 2014.