Endocrine Abstracts (2015) 38 S12.2 | DOI: 10.1530/endoabs.38.S12.2

Selective targeting of the mineralocorticoid receptor in cardiovascular disease

Morag Young

The Hudson Institute of Medical Research, Melbourne, Victoria, Australia.

Sustained mineralocorticoid receptor (MR) signalling promotes cardiac inflammation and fibrosis, which ultimately leads to cardiac failure. While the clinical use of MR antagonists are protective in cardiac disease, hyperkaelemia, and other off target effects have limited their use. In order to identify key MR-dependent mechanisms of heart disease progression that are distinct to normal renal electrolyte control, we have developed a series of tissue selective MR null animal models and determined their responses to the DOC/salt model and other models of cardiac remodelling. We have shown that the MR plays a critical and selective role in the macrophage, cardiomyocyte and in endothelial cells in the progression of cardiac inflammation and fibrosis. Macrophage MR signalling drives the proinflammatory macrophage responses to tissue injury and is central to the onset of fibrosis. The MR in cardiomyocytes has important roles in early chemoattractant signals and determines the hearts response to ischemia reperfusion. Regulation of endothelial cell function by the MR is dependent upon the vascular bed and, but the MR has a central role in macrophage recruitment in these cells. Together, recent data from our lab and elsewhere support a broad but carefully orchestrated role for MR signalling in the cardiovascular system in cardiac pathology and also in the physiological setting. Defining the key mechanistic whereby MR signalling pathways in macrophages and other non-epithelial cells in the cardiovascular system is an essential first step towards identification of therapeutic targets that may preserve potassium homeostasis, especially those cell types in which the MR is most likely acting as a cortisol receptor.

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