Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

The endothelial cell epigenome identifies direct mineralocorticoid receptor target genes in heart failure

L. Deng1, R. Gilsbach2, R. Bednarz3, L. Pollmeier4, A. Mamazhakypov1, C. Bode5, L. Hein1, A. Lother5

1Institut für Pharmakologie, Universitätsklinikum Freiburg, Freiburg im Breisgau; 2Institut für Kardiovaskuläre Physiologie, Johann Wolfgang Goethe-Universität - Fachbereich Medizin, Frankfurt am Main; 3Institute of Cardiovascular Physiology, Goethe University, Frankfurt am Main; 4Albert- Ludwigs-Universität Freiburg, Freiburg im Breisgau; 5Klinik für Kardiologie und Angiologie I, Universitäts-Herzzentrum Freiburg - Bad Krozingen GmbH, Freiburg im Breisgau;

Introduction Cardiac endothelial cells are crucially involved in the pathophysiology of heart failure, controlling angiogenesis and inflammation. Among others, the mineralocorticoid receptor (MR) signaling pathway is a known driver of adverse cardiac remodeling. As a ligand-activated transcription factor MR mediates its effects by regulating gene expression. In this study, we aimed to assess the transcriptional and epigenetic landscape of cardiac endothelial cells at rest and to identify the relative contribution of MR to the changes in gene expression in experimental heart failure.   Methods and results In order to explore their epigenetic landscape, we isolated endothelial cells from mouse hearts by fluorescence- or magnetic bead-assisted cell sorting. Based on ChIP-seq of histone modifications and ATAC-seq data we identified 39.466 regions as active cis-regulatory regions. Using Hi-C, we assessed chromatin interactions and linked active enhancer regions to the contacted promoters of their target genes. Aiming to investigate the role of endothelial cells in heart failure, we assessed their transcriptional profile after transverse aortic constriction (TAC). TAC lead to dysregulation of 2,232 genes in comparison to control mice (q<0.05). As MR takes important roles in heart failure, we treated mice with aldosterone via osmotic minipumps and assessed the resulting gene expression profile. 657 genes showed a concordant regulation after aldosterone stimulation or TAC. By connecting differentially regulated genes to their enhancer regions we could identify transcription factors regulating gene expression. 185 genes exhibited an MR binding motif within the associated enhancers, thus representing direct MR target genes in cardiac endothelial cells. Gene expression analysis revealed that endothelial cell-specific deletion of MR using the Cre/loxP system in mice was able to normalize gene expression of 93 % of the genes differentially regulated by aldosterone stimulation. Conclusion Integrated analysis of the epigenetic landscape and chromatin organization provided insight into the regulation of cardiac endothelial cell gene expression. We defined the contribution of MR to the changes in gene expression during heart failure development and identified cell type-specific enhancers linking MR binding sites to MR target genes.

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