L009 Changes in cardiac transcriptome induced by altered corticosteroid receptor signaling in the heart

Aldosterone plays a major role in the regulation of extracellular volume and blood pressure, through its renal action via the mineralocorticoid receptor (MR). The extra-renal roles of aldosterone/MR in non-epithelial cells (neurones, cardiomyocytes, vessels, adipocytes…) are now intensively investigated. Animal models (aldo/DOCA-salt) and clinical trials (RALES, EPHESUS) evidenced a major pathophysiological contribution of aldosterone/ MR in the cardiovascular system. To evaluate MR cardiac signaling, we analyzed the transcriptomic profile of 2 transgenic mouse models with conditional and inducible overexpression of the MR or of the glucocorticoid receptor (GR) in cardiomyocytes (MHCMR and MHC-GR). Using dedicated cardiochips, we identified 520 cardiac genes that are differentially expressed between control and MHC-MR mice (250 up, 270 down-regulated), and 1232 genes differentially expressed between control and MHC-GR mice (728 up, 504 down-regulated). Some of these genes were validated by real-time PCR, such as Periostin [MHC-MR vs control 10.56±2.2, p=0.02 ; MHC-GR vs control 4.36±1.72, NS], Troponin T3 [MHC-MR vs control 41.66±9.23, p=0.048 ; MHC-GR vs control 1.78±0.41, NS], Fkbp5 [MHC-MR vs control 34.51±6.16, p=0.01 ; MHC-GR vs control 3.33±0.59, p=0.006].We have also compared the effects of aldosterone in the presence or not of different MR/GR antagonists on gene expression in a cardiomyocytes cell line (H9C2 cells) stably expressing the MR, in order to analyze hormone and antagonist specificity.Importantly, some of the MR-specific genes encode for secreted proteins that may represent novel markers of MR activation in circulating blood, including in human pathology