DS0403 - Exploration des systèmes et organes leur fonctionnement normal et pathologique : physiologie, physiopathologie, vieillissement

Regulation, Diagnostics and Therapy focusing on the mineralocorticoid receptor involved in cardiac remodelling – MR-focus

Submission summary

The incidence of heart failure (HF) is increasing because of ageing of the population, while the prevalence at least of systolic HF is also increasing because of improved survival, as a result of life saving therapies. Despite optimal therapy, patients with HF experience disease progression associated with high mortality rates. HF is still the first cause of hospital admission in subjects aged>65 years. The obvious solution for HF epidemics is to prevent new onset HF with therapies directed specifically to mechanistic targets that are involved in the transition to HF. The mineralocorticoid receptor (MR) and its natural ligand, the hormone Aldosterone (Aldo), play important roles during cardiac and arterial remodeling, but the underlying effects are still not understood. MR expression level and activity are modulated by genetic (functional polymorphisms) and epigenetic (miRNA, DNA methylation) “features”. This could participate to MR activation in HF but this has never been explored. MR antagonists are highly recommended for treatment of systolic symptomatic HF, and potentially for HF with preserved ejection fraction. However, adverse effects limit their use in clinical practice. Interfering with mechanistic pathways involved downstream MR activation may provide more focused alternative therapeutic targets. The French and German Partners of this application have identified Neutrophil Gelatinase-Associated Lipocalin (NGAL), Galectin-3 (Gal-3) and specific non-coding RNAs such as microRNAs (miRNAs) as highly focused targets controlling downstream key MR mediated vascular, heart and renal HF mechanisms. The applicants are also involved in the clinical validation of biomarkers corresponding to these selected bio-targets, defining mechanistic bio-profiles potentially useful for prediction of therapeutic response, paving the way to precision HF medicine. Ultimately, targeted MRA therapy may be applied selectively to potential responders, optimizing the clinical risk/benefit ratio in HF prevention

Project coordination

Faiez ZANNAD (INSERM)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

HMS HMS
Cardiovascular Translational Research NavarraBiomed Cardiovascular Translational Research NavarraBiomed
HMS HMS
INSERM 1138 INSERM
INSERM INSERM

Help of the ANR 468,720 euros
Beginning and duration of the scientific project: December 2015 - 36 Months

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