Oral Presentation ESA-SRB Conference 2015

Activation of the mineralocorticoid receptor promotes tissue inflammation in part via the peripheral molecular clock     (#165)

Elizabeth K Fletcher 1 2 , Amanda Rickard 1 , James Morgan 1 , Lea Delbridge 2 , Morag J Young 1
  1. Cardiovascular Endocrinology, The Hudson Institute of Medical Research, Clayton, VIC, Australia
  2. Cardiac Phenomics Laboratory, Department of Physiology, University of Melbourne, Melbourne, Vic, Australia

Activation of the mineralocorticoid receptor (MR) promotes inflammation and fibrosis. Clinical and experimental studies have shown that MR blockade is beneficial in abrogating these effects; however its use is limited due to negative side effects. Thus the identification of cell-specific MR signalling mechanisms may allow for the development of more cardiac-specific MR antagonists. We have shown that in mice null for the MR in cardiomyocytes, regulation of Per2 is lost. Per2 is a member of the peripheral molecular clock (PMC), an anticipatory “transcriptional-translational feedback loop”. Dysregulation of this pathway is associated with cardiovascular disease and may be one potential pathway linking MR activation to cardiac dysfunction. Therefore we hypothesise that the MR regulates the peripheral molecular clock to promote dysregulation of its downstream targets that are involved in cardiac inflammation and fibrosis.

Unineprectomised 8wk old male wild type, Clock∆19mel+(CLK) and cardiomyocyte MR-null mice (myoMRKO) were given 0.9% saline without (VEH) or with deoxycorticosterone (DOC) 7mg/week (n=8-11). Cardiac tissue inflammation and fibrosis by immunostaining showed DOC/salt promoted inflammation and fibrosis in wild type mice. CLK-DOC mice showed elevated baseline values for inflammation and fibrosis (WTVEH vs. CLKVEH macrophages 34%, and tissue collagen 35%), but a blunted response to DOC/salt injury (Fibrosis WT vs CLK 70% vs 40%).  In contrast, myoMRKO mice are protected from DOC/salt cardiac inflammation and fibrosis. We also identified differential gene expression profiles for PMC genes and MR-dependent genes in whole heart between genotypes, indicating a specific subset of PMC genes are regulated by the MR. Of note, systolic blood pressure at 8 weeks was normal in CLK-DOC mice and associated with reduced renal inflammation.

These data suggest that although disruption of the PMC promotes some cardiac remodelling, the MR can regulate the PMC in the heart to drive DOC/salt inflammation and fibrosis and potentially hypertension.