OR04-4 Cardiomyocyte Transcription Is Controlled By Combined Mr And Circadian Clock Signalling.

Abstract

Inappropriate mineralocorticoid receptor (MR) activation promotes cardiac tissue inflammation and fibrosis.We identified a critical pathogenic role for MR activation specifically in cardiomyocytes that revealed a potential interaction between the MR and the molecular circadian clock. While glucocorticoid regulation of the circadian clock is undisputed, MR interactions with circadian clock signalling are poorly defined. We hypothesised that the MR influences cardiac circadian clock signalling, and vice versa. 10nM aldosterone or corticosterone regulated CRY 1, PER1, PER2 andReverbA (NR1D1)gene expression patterns over 24hr. MR-dependent regulation of circadian gene promoters containing GREs and E-box sequences was established for CLOCK, Bmal, CRY 1 and CRY2, PER1 and PER2 and transcriptional activators CLOCK and Bmal modulated MR-dependent transcription of a subset of these promoters. We further demonstrated differential regulation of MR target gene expression in mouse hearts by aldosterone administered at 8AM versus 8PM. Together these data provide proof that MR signalling regulates a subset of circadian gene promoters and MR transcription is influenced by the endogenous circadian transcription factors CLOCK and Bmal. This unsuspected relationship links MR in the heart to circadian rhythmicity at the molecular level and has important implications for the biology of MR signalling in response to aldosterone as well as cortisol, which in the heart can bind MR. Given the undisputed requirement for diurnal cortisol release in the entrainment of peripheral clocks, the present study highlights the MR as an important mechanism for transducing the circadian actions of cortisol in addition to the GR.