Team 3 – Molecular and Cellular Plasticity in Cardiovascular Diseases

Team 3 is headed by Elise Balse  & Sophie Nadaud

Cardiovascular diseases are often intricate diseases that share pathophysiological mechanisms. Remodeling processes are associated with complex rearrangement at the tissue and at the cellular levels. Team 3 aims at identifying the drivers of the molecular and cellular plasticity that characterize cardiovascular remodeling during heart rhythm abnormality (atrial fibrillation), heart failure, senescence and pulmonary hypertension (PH).

We study the role of cardiovascular cells (cardiomyocytes, stem cells, inflammatory cells, endothelial cells), of molecular players (ion channels, cytoarchitectural proteins, sarcolemma), of cellular homeostasis (oxidative stress, energy metabolism). We have tight links with the functional exploration platform Coeur-Muscle-Vaisseaux led by Nathalie Mougenot for cardiovascular phenotyping.

This team is attached to the doctoral school 394 “Physiologie, Physiopathologie et Thérapeutique”.

Principal investigators’ groups:

Elise Balse’s group has contributed to understanding the dynamics of surface expression of cardiac ion channels and the molecular determinants of their targeting in specialized domains of cardiac myocytes. The group will continue investigating these processes in relation with the microarchitecture of cardiac myocytes in normal and diseased myocardium. The work combines cardiomyocyte isolation and culture, molecular biology, viral vectors, electrophysiology techniques (patch-clamp, microelectrode), biochemistry, immuno-histo/cytochemistry, and cellular and molecular imaging approaches (3D-deconvolution, TIRF, light sheet).

Sophie Besse and Bruno Riou’s group has identified different mechanisms contributing to the altered cardiac response to β-adrenergic stimulation during senescence and/or diabetes. This group is now investigating the regulatory pathways induced by age-associated oxidative stress and inflammation, and implicated in the transition to heart failure. The project includes hemodynamic studies, contractility measurements in isolated perfused heart and atrial trabeculae, and biochemistry and immuno-histo/cytochemistry techniques, in aged rat and human models.

Stephane Hatem’s group has uncovered the contribution of epicardial stem cells to atrial fibroadipogenic remodeling leading to atrial fibrillation. The group aims now at identifying the signaling switches that regulate the differentiation of human epicardial stem cells and the remodeling of the atrial subepicardium. The group has also started to analyze the role of cardiac metabolism in regulating atrial fibroadipogenic remodeling and electrical properties. In addition to biochemistry, immuno-histo/cytochemistry techniques, the group is using metabolomics and lipidomic approaches, human and murine epicardic progenitor cells culture, flow cytometry and electrophysiology.

Sophie Nadaud’s group has described new vascular progenitors which contribute to the remodeling of pulmonary vessels during pulmonary hypertension. The group is now studying the regulatory signals that lead to the recruitment of these progenitors and the formation of new vascular smooth muscle cells. The work combines transgenic mouse models, lineage tracing mouse models, hemodynamix studies, flow cytometry, murine vascular progenitor cell culture, molecular biology and biochemistry, immunofluorescence and histology techniques.

Catherine Pavoine’s group has established that a macrophage population plays a protective role against heart failure development during early adaptive cardiac hypertrophy. The group is now seeking to identify the origin and role of macrophages recruited and to determine the signals secreted by these macrophages during early adaptive cardiac hypertrophy which could limit adverse remodeling to heart failure. The project involves mouse models, cardiomyocyte calcium imaging, flow cytometry, RNAseq and biochemistry, immuno-histo/cytofluorescence techniques. Echocardiographic parameters of the animals are analyzed with the Coeur-Muscle-Vaisseaux platform (Dir. Nathalie Mougenot).

Florent Soubrier’s group has identified the gene, EIF2AK4, for hereditary Pulmonary Veno-Occlusive Disease and is now investigating the cellular and molecular mechanisms underlying the occurrence of the heritable form of Pulmonary Veno-Occlusive Disease due to mutation of this gene. The project involves an EIF2AK4 KO rat model, hemodynamic studies, flow cytometry, endothelial cell isolation and culture, and omics. This group seeks to identify new predisposing genes to PH by genome wide sequencing, such as the BMP10 gene recently identified by this group.

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