Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

Loss of the peripheral molecular clock blunts the cardiac response to mineralocorticoid induced cardiovascular disease (#196)

Elizabeth K Fletcher 1 2 , James Morgan 1 , Lea M Delbridge 2 , Morag J Young 1
  1. Cardiovascular Endocrinology Laboratory, MIMR-PHI Institute of Medical Research, Clayton, Vic, Australia
  2. Cardiac Phenomics Laboratory, Department of Physiology, University of Melbourne, Melbourne, Vic, Australia

Clinical and experimental studies demonstrate that activation of the mineralocorticoid receptor (MR) in the heart leads to increased inflammation, fibrosis and endothelial dysfunction. These effects can be abrogated by MR antagonists. MR antagonists however, have limited use due to negative side effects. Consequently the identification of cell-specific MR signalling mechanisms may allow for the development of more specific cardiac MR antagonists. One potential mechanism downstream of MR is the peripheral molecular clock (PMC). The molecular clock is a transcriptional translational feedback loop comprising of core “clock genes” which bind to and regulate numerous downstream cardiac genes. Dysregulation of the peripheral molecular clock genes in the heart leads to altered transcription of cardiac target genes, contributing to many aspects of cardiovascular disease. We hypothesize that activation of cardiomyocyte MR leads to dysregulation of the peripheral molecular clock resulting in cardiac inflammation, fibrosis and dysfunction.

Unineprectomised 8wk old male wild type and Clock∆19mel+(CLK) mice were maintained on 0.9% saline without (VEH) or with deoxycorticosterone (DOC) 7mg/week pellet (n=8-11). Systolic blood pressure (SBP) was recorded at eight weeks. Heart tissue was analyzed for inflammation: macrophage and CD3+ T-cell recruitment, and fibrosis. Quantitative RT PCR was used to assess expression of PMC genes and cardiac markers of fibrosis and inflammation in the whole heart.

Results showed that inflammation and fibrosis are elevated in CLK-VEH mice compared to WT-VEH (macrophages 34%, and tissue collagen 35%), while WT-DOC was blunted when compared to CLK-DOC due to an elevated CLK-VEH baseline. SBP was blunted in CLK-DOC mice by decreased activated renal macrophages, while regulation of PMC genes in response to DOC/salt was lost in CLK mice.

Loss of the peripheral molecular clock increases inflammation and fibrosis, but blunts the response to DOC/salt. While SBP is normal in CLK mice, the pressor response to DOC/salt is lost.