7722 Temporal mineralocorticoid receptor activation regulates the molecular clock and transcription of cardiovascular disease modulators in myeloid cells

Abstract Disclosure: M.J. Young: None. S. Heanue: None. M. Kanki: None. D.W. Ray: None. J. Morgan: None. T.J. Cole: None. The mineralocorticoid receptor (MR) is an established target in the treatment of heart failure, as a mediator of cardiac inflammation and fibrosis. We recently identified a bidirectional regulatory role for the MR and the peripheral molecular clock in cardiac cells. We have also demonstrated a novel role for the MR in macrophages/monocytes in the progression of cardiac inflammation and fibrosis. Given that immune cells are implicated in cardiac pathology, we investigated whether the MR modulates temporal transcription of the molecular circadian clock and inflammatory mediators in the spleen from myeloid MR null mice (MyMRKO), and in immortalised bone marrow derived cells (BMDCs) RNAseq and RT-qPCR analysis of whole spleen from wild type (WT) or MyMRKO revealed differential expression of the clock genes Per2, Cry1, REV-ERBα, and Dbp predominantly at ZT0 and ZT4 compared to ZT12 and ZT16. 10nM aldosterone or corticosterone modulated the 24hr pattern of expression of Per2, REV-ERBα and other clock components in cultured BMDCs, supporting a direct role of MR in timekeeping. MR modulation of genes involved in the proinflammatory response in macrophages such as iNOS, IL-1β, Arg-1, IL-10, CCL2 and Spp1 was more evident at the start of the ‘lights on’ phase in mice, suggesting that low circulating corticosterone at these times allows for a more dominant MR response as a result of preferential binding. Genes related to PPARγ signalling, a key pathway in the development of cardiovascular disease, also demonstrated MR-dependent regulation in a temporal manner. Significant differences in temporal MR modulation were evident between males and females, implying a role for sex hormones in the modulation of circadian signalling and myeloid inflammatory responses in the context of MR-regulated transcription. Our findings underscore the dynamic influence of MR signalling on circadian rhythms and inflammatory pathways in myeloid cells, highlighting potential sex-based differences and offering insights into its pivotal role in cardiovascular disease pathogenesis. Presentation: 6/3/2024