Lightning Talk + Poster ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Temporal mineralocorticoid receptor activation regulates the molecular clock and transcription of cardiovascular disease modulators in myeloid cells. (#503)

Morag J Young 1 2 , Seamus Heanue 1 3 , Monica Kanki 1 , Tim J Cole 4 , David W Ray 5 , James Morgan 6
  1. Baker Institute, Melbourne, VIC, Australia
  2. University of Melbourne and Baker Institute Department of Cardiometabolic Health and Disease , University of Melbourne, Melbourne
  3. Monash Health , Melbourne
  4. BDI, Biochemistry , Monash University , Melbourne
  5. Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University , Osford, UK
  6. Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research , Melbourne

The mineralocorticoid receptor (MR) is an established target in the treatment of heart failure, as a mediator of cardiac inflammation and fibrosis. We have shown that the MR in macrophages/monocytes plays a critical role in the progression of cardiac inflammation and fibrosis. Recently, we identified a bidirectional regulatory role for the MR and the peripheral molecular clock in cardiac cells. Given that immune cells can mediate cardiac pathology, we investigated whether the MR also modulates temporal transcription of the molecular circadian clock and inflammatory mediators in spleens from myeloid MR null mice (MyMRKO), and in immortalised bone marrow derived cells (BMDCs). Whole transcriptome analysis of spleens from wild type (WT) or MyMRKO revealed differential expression of clock genes Per2, Cry1, REV-ERB⍺, and Dbp at ZT0 versus ZT12. 10nM aldosterone or corticosterone modulated the 24hr expression pattern of Per2, REV-ERB⍺ and other clock components in cultured BMDCs, supporting a direct role of MR in timekeeping. MR modulation of genes involved in inflammatory responses in macrophages such as iNOS, IL-1β, Arg-1, IL-10, CCL2 and Spp1 was evident at the start of the ‘lights on’ phase in mice. Genes related to PPARγ signalling, a key pathway in the development of cardiovascular disease, also demonstrated MR-dependent regulation in a temporal manner. Temporal MR modulation of gene targets differed between males and females. Our findings underscore the dynamic influence of the MR on circadian rhythms and inflammatory pathways in myeloid cells, highlighting sex-based differences and offering insights into its pivotal role in cardiovascular disease pathogenesis.