The mineralocorticoid receptor (MR) is a ligand-activated transcription factor from the nuclear receptor family. The physiological function of MR is the control of water and electrolyte balance, primarily via the regulation of sodium channels such as ENaC in epithelial cells of the kidney and colon. In addition, MR has strong inflammatory and pro-fibrotic properties and thus unfavorable impact on heart and kidney function. MR antagonists are widely established in the treatment of chronic heart failure and renal insufficiency. However, currently available compounds are associated with an increased risk of adverse effects such as hyperkalemia, which considerably limits their clinical applicability [1]. During the past two decades, mouse models with cell type-specific deletion of MR demonstrated that the pathological effect of MR is primarily mediated via cardiomyocytes, endothelial cells cells, and immune cells [2]. Selective blockade of the MR signaling pathway in these cell types could therefore separate the pathological inflammatory effects from the physiological function of MR.

Endothelial cells are considered a central hub of cell-cell communication in the heart. They form capillaries that are crucial to maintain the high oxygen and energy demand of cardiomyocytes. As endothelial cells represent the inner layer of the vasculature, they have an important barrier function, control the migration of immune cells from the bloodstream, and regulate tissue homeostasis [3]. Gene expression is controlled by transcription factors binding to enhancers and promoters. We created a comprehensive atlas of chromatin accessibility, histone modifications, and 3D chromatin organization and determined enhancer-promoter interactions in cardiac endothelial cells and confirmed the functional relevance of enhancer-promoter interactions by CRISPRi-mediated enhancer silencing. A systematic comparison of mouse models representing different cardiovascular risk factors identified MR as common regulator of pathological gene expression in cardiac endothelial cells and predicted direct MR target genes [4]. We conclude that epigenetic modulation may be a promising strategy towards selective targeting of MR-dependent pathological gene expression.