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

Cardiac Ca2+ signaling and mineralocorticoid network – Calsignaldo

Submission summary

Even if the last half-century had witnessed the spectacular advances in the prevention, diagnosis, and management of cardiovascular diseases, heart failure (HF) is a notable exception. Despite therapeutic improvements, the mortality remains unacceptably high, with sudden cardiac deaths, due to ventricular arrhythmias (VA) in which aberrant cardiac Ca2+ fluxes are seminal, a major cause of death.
Clinical and experimental studies pointed out a detrimental association between aldosterone/Mineralocorticoid Receptor (MR) and life-threatening VA, but the associated signaling pathways and underlying mechanisms are still elusive. Our recent works demonstrated a specific Ca2+ channel remodeling (namely, upregulation of the L-type Ca2+ channels [LTCC] and the Store-Operated Ca2+ entry [SOCE]) involved in VAs, as main cardiac target of mineralocorticoid signaling. However, the cardiac cellular effects of aldosterone/MR remain to be more precisely defined as well as the molecular mechanisms involved in cardiac MR pro-arrhythmic effects.
Our working hypothesis is that MR, as a ligand-dependent transcription factor, controls the Ca2+ channels expression and/or function and possibly other factors conferring susceptibility to life-threatening cardiac arrhythmias.
Through interdisciplinary approaches and shared materials (e.g., neonatal and adult cardiomyocytes from healthy and pathological animal models, embryonic stem cell-derived cardiomyocytes, transfected and immortalized cell lines, transgenic animals, antibodies, transcriptional regulation) from two internationally recognized leading and complementary partners that conduct synergetic state-of-the art research in the field of function of cardiac ion channels and arrhythmia (Inserm UMR-S1180 partner 1, Dr Jean-Pierre Benitah) and MR biology (Inserm UMR-S1185 partner 2, Dr Marc Lombès), we aim at analyzing the cardiac network of Ca2+/MR signaling in cardiomyocytes, focusing on already identified potential targets (Ca2+ channels) and modulators, but also seeking for identification of novel signaling pathways by innovative strategies.
Our project will focus on
1/ the transcriptional control of LTCC expression by aldosterone/MR using chromatin immunoprecipitation (ChIP), as well as by assessing in vivo the relevance of this regulation on a transgenic mouse line expressing whole body luciferase reporter gene under the control of the promoter sequence of rat LTCC using in vivo bioluminescence;
2/ the Store-Operated Ca2+ Channels as new targets of aldosterone/MR in cardiomyocytes using combined functional and molecular approaches in adult rat cardiomyocytes and by an in vivo assay in healthy and pathological mouse models, notably a mouse model with cardiac-specific dominant negative of Orai1-mediated SOCE;
3/ the identification of new MR specific target genes in cardiomyocytes using ChIP coupled with DNA sequencing (ChIP-seq) in healthy and pathological mouse models;
4/ the cardiac specific molecular mechanisms of MR activation and inactivation by developing affinity purification coupled to mass spectrometry (AP-MS).
Our research program will allow to fill the gap of knowledge between beneficial effects of anti MR therapy and the mechanisms of MR activation (post-translational modifications, coregulators), identifying the molecular and pathophysiological consequences of MR activation (novel cellular targets and signaling pathways). The achievement of this project program will provide basic knowledge on the yet poorly defined MR in the cardiomyocyte context, what might be used for future development of tissue-specific MR therapies to alleviate one of the largest health burdens to the modern society, i.e. malignant ventricular arrhythmias.

Project coordination

jean-pierre benitah (Laboratoire de Signalisation et Physiopathologie Cardiovasculaire)

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

INSERM UMR-S 1180 Laboratoire de Signalisation et Physiopathologie Cardiovasculaire
INSERM UMR-S 1185 Laboratoire de Signalisation Hormonale, Physiopathologie Endocrinienne et Métabolique

Help of the ANR 374,664 euros
Beginning and duration of the scientific project: September 2015 - 36 Months

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