MIRENDO

Aldosterone (aldo), a mineralocorticoid hormone, is the main regulator of sodium balance and blood volume; Aldo binds to a ligand-activated transcription factor, the mineralocorticoid receptor (MR), which trigger the transcription of target genes. The intervention of still unknown tissue-specific cofactors is probably necessary to ensure aldo-specific effects. New cellular targets of this hormone have been discovered, extending its actions to the cardiovascular system. In particular, the endothelium express both MR and the glucocorticoid receptor (GR). The RALES and EPHESUS clinical trials demonstrated that the addition of MR antagonists to standard care markedly reduced the overall and cardiovascular mortality in patients with heart failure. However cellular targets and molecular /pathophysiological events underlying these benefits are unknown but the vasculature has been proposed to be a key player. The signaling pathways involved in mineralocorticoid effects remain elusive because: 1) most of the proposed signaling pathways have been identified in cultured cells; 2) their identification using pharmacological approaches is hampered by the pleiotropic effects of MR activation. The vascular endothelium, whose surface is about 300 m2, is not just a simple barrier but plays a key role in the local control of vascular tone, adequate organ perfusion, blood pressure by releasing vasoactive autacoids and is involved in coagulation process as well as atherosclerosis. Endothelial cells (EC) form a multifunctional signal-transducing surface that performs different tasks. EC regulates the permeation of various metabolites, macromolecules and gases as well as autocrine and paracrine factors. The endothelium is also proposed to be a major source of circulating, accessible biomarkers. Indeed, the use of biomarkers will be a major breakthrough in the next decades for clinical practice, helping to adapt therapeutics to individual patient and not the opposite, hoping to improve efficiency of treatments and limitation of their side-effects. To date no biomarkers of MR activation have been described. Our global working hypothesis is that the endothelium is 1) a major target of aldo involved in several pathological conditions, 2) a therapeutic target involved in the strong beneficial effects of pharmacological MR antagonism, 3) a source of biomarkers of MR activation useful as theranostic tools. The main strength of this integrated project is to combine complementary and synergistic expertises of partners that either i) provided major contributions to the understanding on Aldo action and MR activation in CV pathophysiology and its clinical consequences, ii) developed relevant strategies in other fields of research, i.e. epigenetic control of cancer, iii) could develop pre-clinical trial in veterinarian medicine to analyze the correlation between biomarkers and MR activation in canine cardiac failure. The proposed project is based on several original approaches, integrating molecular and functional basic investigations as well as translational clinical research based on our findings. Wevwill take advantage of a series of dedicated experimental models in which the level of MR or GR receptors is changed in a selected tissue (i.e. endothelium) to better understand the mechanisms whereby aldo/MR acts in CV disease. At variance with other research groups working on this topic, the use of proprietary transgenic models with conditional control of MR/GR expression in EC i) limits the confounding effects seen with pharmacological approaches due to the pleiotropic effects of mineralocorticoids, ii) mimics the increased MR expression reported in various pathophysiological situations (heart failure, hypertension). Together, we plan to explore 1) the role of endothelial Aldo/MR activation in vascular pathophysiology; 2) the tissue-specific gene programs modulated by MR activation in vascular tissues, 3) the underlying tissue-specific coactivators recruted to explain this specific molecular signatures using innovative proteomic approaches to define transcription factor interacting partners; 4) the clinical relevance in veterinarian and human medicine of biomarkers identified in these experimental models, which could be clinically useful as theranostic tools to select patients with CV diseases most likely to benefit from pharmacological MR antagonism. The ambitious and innovative aspects of this multidisciplinary proposal is based on i) complementary approaches and expertises 2) constant shuttles between fundamental research, experimental pathophysiology and clinical studies, allowing crossfeeding between all components, iii) strong willingness to stimulate industrial partnership based on intellectual property and innovative results, allowing future prospective clinical studies for the biomarkers or search for novel drugs targeting MR and its molecular targets.