S1-1 The Role and Regulation of Mineralocorticoid Receptor Activation in Heart Failure

Abstract

Mineralocorticoid receptor (MR) activation by either administration of exogenous mineralocorticoids, or by endogenous glucocorticoids, promotes oxidative stress, vascular inflammation and cardiac fibrosis in experimental animals. These studies suggest potential mechanisms for the benefits observed in recent large scale clinical trials investigating the cardioprotective effects of MR antagonists given in conjunction with current best practice. Given that few patients showed elevated plasma aldosterone, novel mechanisms involved in activating the MR in the failing heart are now being investigated. We have investigated the contribution of specific cell types to MR-mediated cardiac pathology using Cre-Lox technology to create tissue specific MR knockouts mice. Our data suggests that MR signalling in macrophages contributes to the regulation of proinflammatory and profibrotic genes associated with the onset of cardiac fibrosis. Importantly, macrophage MR null mice given DOC/salt for 8 weeks show no increase in cardiac fibrosis and systolic blood pressure, in contrast to wild type littermates. Given that macrophage recruitment is equivalent in MR macrophage knockout mice and wild type mice these data suggest that macrophage MR may play a distinct role in tissue remodelling but that MR activation elsewhere in the cardiovascular system is also important. Selective modulators of the MR that are specifically directed towards non-epithelial cardiovascular tissue would increase tissue protection without the side effects associated with renal MR blockade. Moreover, activation of the MR by other ligands would argue for the use of MR antagonists in renal and cardiovascular protection even when plasma aldosterone is normal.