Team 3 - Molecular and Cellular Plasticity in Cardiovascular Diseases
For more than 15 years, our group ( https://recherche-Cardiovascular-metabolique.fr ) has been involved in deciphering the genetic and cellular mechanisms of these diseases. We have recently identified the involvement of new genetic variants thanks to the study of the whole genome. This new knowledge allows us to better understand these diseases, to progress towards personalized medicine, and provide a glimpse of new therapeutic approaches.
Current research
Topic 1 - Molecular mechanisms of ion channel membrane expression in cardiac myocytes – Elise Balse
The functional expression of ion channels in the myocyte membrane determines the shape and duration of the action potential, thereby controlling the effective refractory period of the myocardium. The expression of ion channels can be disrupted at several levels, from their biosynthesis to their final targeting in the membrane.
We study :
- changes in the trafficking machinery in acquired heart disease and their role in arrhythmogenic substrate formation. (Boycott et al., PNAS 2013; Melgari et al., JMCC 2020);
- regulation of myocyte electrical and structural polarity driven by ion channel partner proteins (Eichel et al., Circ Res 2016; Beuriot et al., Heart Rhythm 2020).
Theme 2 - Mechanisms of age-related cardiac remodeling: Role of FoxO and NFkB pathways – Sophie Besse and Bruno Riou
Our group is interested in the mechanisms involved in cardiac aging (Carillion et al., 2015; Launay et al., 2017). The production of reactive oxygen species (ROS), a hallmark of aging, modulates the activation/inactivation of different transcription factors such as NF-κB and FoxOs which, in turn, regulate many cellular pathways including l inflammation, necrosis/apoptosis, ion homeostasis, myocyte hypertrophy and extracellular matrix remodeling. We are currently studying age-associated alterations of FoxO and NF-κB pathways in rodent hearts but also in human atria that remain largely unexplored during aging and age-associated diseases such as atrial fibrillation and diabetes.
Theme 3 – Pathophysiology of atrial cardiomyopathy and atrial fibrillation – Stéphane Hatem
A number of clinical studies have established that the accumulation of fatty tissue on the surface of the atrium is a major risk factor for atrial fibrillation, especially in metabolic disorders such as obesity (Hatem JACC 2016). Stéphane Hatem’s group was the first to demonstrate a causal link between epicardial adipose tissue and atrial fibrillation. Recently, they identified a subpopulation of epicardial progenitors committed to adipocyte or fibroblast differentiation (Suffee, Circ Res, 2020). They are now characterizing the regulation of these signaling pathways that mediate such change.
Theme 4 – The role of immune and inflammatory cells during cardiovascular remodeling leading to heart failure – Catherine Pavoine
Our group is interested in cardiac remodeling caused by activation of the sympathetic nervous system or in response to pressure overload. We focused on hypertrophy and fibrosis responses leading to heart failure and the time-dependent beneficial and detrimental role of inflammatory signaling. We have highlighted the early protective paracrine role of cardiac macrophages (Keck et al., 2019). We recently identified the CX3CL1/CX3CR1 axis as a determinant in hypertrophic remodeling (Flamant et al, 2021 in press) and we are now characterizing the evolution of the transcriptomic and lipidomic profile of cardiac macrophages.
Theme 5 – Cellular and molecular plasticity during pulmonary vascular remodeling in pulmonary arterial hypertension – Sophie Nadaud
Our group is interested in cellular and molecular factors involved in alterations of vascular structure (remodeling). We are particularly studying the origin of new smooth muscle cells produced during pulmonary hypertension. It is a rare and devastating disease, with no curative option, characterized by occlusive remodeling of the distal pulmonary vasculature which ultimately leads to right heart failure. We have identified pulmonary resident vascular progenitor cells that proliferate and generate new vascular smooth muscle cells (Dierick, Circ Res 2016). We have recently demonstrated that the proliferation of these progenitor cells is under the control of the PDGFRα pathway.
Theme 6 – Cellular and molecular mechanisms underlying the development of pulmonary veno-occlusive disease – Florent Soubrier
Our projects focus on:
the plasticity of the cellular composition of cardiovascular tissues. In particular, we are studying the ability of progenitors and stem cells to be recruited, to differentiate into various mesenchymal cell lineages and to contribute to auricular and vascular remodeling.
the plasticity of macromolecular protein complexes regulating cardiac function and their role in pump dysfunction and arrhythmias. We focus on the regulation of ion channel trafficking and targeting in cardiomyocytes.
the role of cellular metabolic changes in regulating myocardial remodeling and atrial electrical properties.
the role of immune and inflammatory cells during cardiovascular remodeling leading to heart failure. We are studying the mechanisms of the protective role of macrophages during early adaptive cardiac hypertrophy.
the role of oxidative stress and inflammation during age-associated cardiovascular remodeling and the transition to heart failure.
the role of GCN2 gene mutation in the development of pulmonary veno-occlusive disease, a specific form of pulmonary hypertension.
Major Publications
Team 3 Rewards
Stéphane Hatem / Alain Castaigne – Award – 2018
Florent Soubrier / Jean Valade Award – 2014
Lamonica Cardiology – Award – Academy of Sciences – 2017
France Diérick / Marion Elizabeth Brancher – Award – 2017
