Cell type-specific function of the mineralocorticoid receptor in pulmonary hypertension and associated right heart failure

• Applicant: Privatdozent Dr. Achim Lother
• Subject Area: Cardiology, Angiology
• Term: from 2019 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 428371883

Pulmonary hypertension (PH) and subsequent right ventricular remodeling are associated with high morbidity and poor outcome. Aldosterone and its receptor, the mineralocorticoid receptor (MR), are key mediators of cardiovascular disease. Preclinical and early clinical data show beneficial effects of MR antagonists on pulmonary artery pressure and right ventricular function. However, their clinical use is limited by adverse effects on renal function. A precise understanding of the cellular and molecular function of MR in PH and right ventricular remodeling might foster new therapeutic innovation to separate beneficial from adverse effects.The pathophysiology of PH and right ventricular failure involves various cell types in the pulmonary vasculature and the heart that express MR. As a ligand-activated transcription factor, MR mediates many of its effects via regulation of gene expression. Chromatin accessibility and transcriptional activity of MR are modulated by epigenetic modifications and interaction with other transcription factors. The aims of this project are 1) to identify the cell types in which MR is relevant for PH and right ventricular remodeling using cell type-specific MR deletion mouse models, 2) to determine molecular mechanisms that modulate transcriptional control by MR by deciphering the specific transcriptome and epigenome of these cells, and 3) to evaluate the impact of pharmacological MR inhibition on transcriptomic and epigenetic changes in PH and right ventricular remodeling.The mechanistic insights gained in this project will set the basis for future studies that aim to identify new pharmacological targets and might lead to the development of cell type-specific inhibitors of the MR signaling pathway for the treatment of PH and right ventricular remodeling.

• DFG Programme: Research Grants