TEAM F. Lezoualc’h

SIGNALING AND PATHOPHYSIOLOGY OF HEART FAILURE AND AGING

Our team associates researchers and clinicians with a common interest in better understanding the mechanisms involved in heart failure and cardiac aging. Our final goal is to identify relevant drug targets to treat or block the progression of heart failure.

TEAM Members

 
Tous / AllTeam leaderResearchersCliniciansPost Doctoral fellowsStudentsTechnical staff
Team Leader

Frank LEZOUALC’H

Associate profesor

Caroline CONTE

Bertrand MARCHEIX
Clinician

Bertrand MARCHEIX

Clinician

Clément DELMAS

Clinician

Olivier LAIREZ

Jean PORTERIE
Clinician

Jean PORTERIE

Post-Doctoral fellow

Yohan SANTIN

Post-Doctoral fellow

Karina FORMOSO

Post Doctoral fellows

Maximin DETRAIT

Doctorante

Jessica RESTA

Engineer

Dorian BERGONNIER

Doctorant

Ezechiel AGBEGBO

Technician

Françoise PUJOL

Team Leader

Frank LEZOUALC’H

INSERM research director (DR1) INSERM

Frank Lezoualc’h is expert in the identification of novel therapeutic target for heart failure. He has provided significant contributions elucidating the role and signaling of the cyclic AMP Epac proteins and Carabin in cardiac disease. He was pioneer in the characterization of Epac1 pharmacological inhibitors and their potential use as therapeutic molecules in several diseases.

Career path
Frank Lezoualc’h obtained his PhD in Molecular Endocrinology from the University Pierre & Marie Curie, Paris in 1995. After a postdoc at the Max-Planck Institute in Munich, he developed his own group in molecular cardiology at Inserm, University of Paris-Saclay in 2000. He joined I2MC of Toulouse in 2010 as research director at Inserm and team leader.

Main domains of expertise
Signaling, cardiac remodeling, cardiovascular diseases, therapeutic innovation.

Associate profesor

Caroline CONTE

Associate Professor in Molecular Biology, University of Toulouse III

Caroline Conte is interested in the epigenetic mechanisms involved in the gene reprogramming induced by cardiac stress. The aim of this work is to identify new molecular actors of heart failure.

Career path
Caroline Conte obtained her PhD in Molecular and Cellular Biology at the University of Auvergne, France, in 2001. She then completed a post-doctoral fellowship in Basel, Switzerland in the pre-clinical research department of Hoffmann-La Roche before being recruited as a junior researcher at Inserm in 2005 and as an associate professor in molecular biology at the University of Toulouse III in 2009. She joined the I2MC in 2014.

Main domains of expertise
Mechanisms of gene expression regulation (transcription/translation) in different contexts (cardi-ology, immunology, angiogenesis), Vectorology.

Clinician

Bertrand MARCHEIX

Clinician

Clément DELMAS

MD, Associate Professor of Cardiology

Career path
Clément DELMAS obtained his MD in 2012 and graduations in Cardiology (2013) and Critical care medicine (2015). He is Associate Professor in the Department of Cardiology at the University Hospital of Toulouse (2021). He is involved in the management of acute and/or chronic severe hpatients in Intensive Cardiac Care Unit and in the Chronic and Acute Mechanical Circulatory support team. He is vice-president of the Emergency and Intensive Cardiac Care Working group of the French Society of Cardiology.

Main domains of expertise
Heart Failure, Cardiogenic shock, Myocarditis, Takotsubo syndrome, Mechanical circulatory support

Clinician

Olivier LAIREZ

MD, PhD, Professor of Cardiology

Career path
Olivier LAIREZ received his MD (2008) and PhD (2010) degrees from the University of Toulouse, and a master in health economics (London School of Economics, 2021). He has both specialities of cardiologist and nuclear physician. After 2 years of postdoc at Icahn School of Medicine at Mount Sinai (NY), he was appointed associate professor of Cardiology in 2014 and then in 2018, he got a position of professor at the University Hospital of Toulouse. He is currently heading the Cardiac Imaging Center and the Cardiac Exploration Unit of the Rangueil University Hospital. His current research interests are focused on heart failure, cardiomyopathies and cardiac imaging applied to the exploration of the myocardium.

Main domains of expertise
Heart failure, Cardiac imaging, cardiac amyloidosis, Heart failure with preserved ejection fraction

Clinician

Jean PORTERIE

Post-Doctoral fellow

Yohan SANTIN

Postdoctoral Fellow

Yohan Santin is working in the team as a Postdoctoral fellow in the field of anthracycline cardiotoxicity and in the development of novel therapeutic strategies. He is also involved in the Regional/European INSPIRE project, where he works as a Project Manager.

Career path
Yohan Santin received his PhD in Pharmacology from the Paul Sabatier University, Toulouse, France, in 2019. His works aimed at understanding the role of mitochondrial oxidative stress in the onset of post-infarction heart failure.

Main domains of expertise
Oxidative stress, Mitochondrial function, Autophagy, Aging.

Post-Doctoral fellow

Karina FORMOSO

Postdoctoral Fellow

Karina Formoso is currently involved in a project that focuses on determining the molecular pathways underlying cardiac aging, in particular senescence, in the heart. She also evaluates the role of EPAC1 protein in cardiac pathophysiology.

Career path
Karina Formoso received her PhD in molecular biology and biotechnology in the National University of San Martin, Argentina, in 2016. After she joined as a postdoctoral fellow to the group of Prof. Lutz Birnbaumer at the Catholic University of Argentina.

Main domains of expertise
Aging, senescence, cell signalling.

Post Doctoral fellows

Maximin DETRAIT

Postdoctoral fellow

Maximin Détrait is working in the team as a Postdoctoral fellow in the field of cardiovascular disease. He studies cyclic AMP signalization and the Epac1 partners using among others omics analysis.

Career path
Maximin Détrait received his PhD in physiology – pathophysiology – pharmacology from the Grenoble Alpes University, France, in 2020. His work aimed at understanding the impact of intermittent hypoxia-induced cardiac sympathetic activity on the ischemic cardiomyopathy aggravation.

Main domains of expertise
Ischemic cardiomyopathy, cardiac remodeling, sympathetic activity, calcium homeostasis.

Doctorante

Jessica RESTA

PhD Student

Jessica Resta works in the field of bladder cancer. Her thesis project is carried out in collabora-tion with Urosphere and her work consists in the evaluation of the therapeutic effect of MAOs inhibitors capable of interfering with the enzymatic activity in the rat tumour cell line AY27.

Career path
Jessica Resta obtained her Masters II in Biological Sciences from the University of Milan, Italy, in 2018. The subject of the studies was the modification of pro-angiogenic differentiation in CD34 + cells by epigenetic mechanisms. In 2019, she began her thesis course at Paul Sabatier University, Toulouse, France, in collaboration with the company Urosphere. Her work aims to understand the role of monoamine oxidases in chronic diseases associated with aging.

Main domains of expertise
Bladder Cancer, Oxidative stress, Mitochondrial function, Aging.

Engineer

Dorian BERGONNIER

Assistant Engineer (Fixed-term contract)

Dorian Bergonnier works as an assistant engineer, collaborates in many of the projects of the team. Among them he assists in the study of EPAC1 role in cardiac pathologies and in the molecular characteri-zation of pharmacologial tools to modulate EPAC’s activity.

Career path
Dorian Bergonnier obtained a master’s degree in pathophysiology at Paul Sabatier University, Toulouse, France in 2020. After working on the WE-MET proteomics platform, he joined the team in November 2020 and holds the position of assistant engineer.

Main domains of expertise
Biochemistry, cell culture and general molecular biology techniques.

Doctorant

Ezechiel AGBEGBO

PhD Student

Career path
Ezechiel AGBEGBO received his master degree in Pharmacology from the Paul-Sabatier University, Toulouse in 2021. He joined our team in October 2021 as a PhD Student in the field of signaling and cardiac pathophysiology.

Main domains of expertise
Biochemistry, molecular pharmacology, animal experimentation

Technician

Françoise PUJOL

Technician/Lab manager

Françoise was recruited in Inserm in 2000 and is a founding member of our team.

Main domains of expertise
Cell biology, molecular biology, animal experiments.

New therapeutic targets in heart failure with preserved ejection fraction

Karina Formoso, Maximin Détrait, Dorian Bergonnier, Olivier Lairez, Bertrand Marcheix,  Clément Delmas, Jean Porterie , Jessica Resta, Yannis Sainte-Marie, Yohan Santin, Frank Lezoualc’h

 Heart Failure (HF) with preserved ejection fraction (HFpEF) is the most common form of HF and is favored by aging, diabetes and obesity. It is characterized by impaired filling and relaxation of the heart, for which there is no effective therapy. Understanding the mechanisms regulating cardiac remodeling (e.g hypertrophy, senescence, cell death) in the context of diabetes / obesity and aging could pave the way for new treatments of HFpEF. Our team has characterized molecular events that are strongly involved in cardiac remodeling. These “signalosomes” are located in different subcellular compartments and involve the cAMP-sensitive protein, Epac1 or the monoamine oxidase-A (MAO-A). Pioneers in the discovery of these proteins in the heart, we have acquired a strong expertise in these targets and developed a panoply of pharmacological tools and animal models which could allow the development of new therapeutic strategies.

KEY SIGNALING NETWORKS INVOLVED IN THE DEVELOPMENT OF HEART FAILURE AND AGING.

We have identified new signaling pathways involved in heart failure and aging. Our goal now is to dissect the signalosomes of Epac/Carabin/MAO-A proteins in order to under-stand how these proteins influence cell fate. We analyse their molecular events in different compartments of the cardiomyocyte and determine their protein network and target genes. Our approach is multidisciplinary: we are seeking pharmacological modulators of these therapeutic targets and develop new experimental models of HF.

CARDIAC THERAPIES WITH NEW EPAC1 INHIBITORS

 

Karina Formoso, Maximin Détrait, Olivier Lairez, Clément Delmas , Dorian Bergonnier, Frank Le-zoualc’h

We have provided evidence that Epac1 genetic inhibition is cardioprotective in various cardiac stress condi-tions such as myocardial ischemia. These data suggest that pharmacological inhibition of Epac1 could be beneficial for the treatment of cardiac diseases. To test this assumption, we have established various func-tional tests and have isolated by high through put and virtual screening assays the first two families of Epac1 selective pharmacological inhibitors. The first generation of Epac1 inhibitor named CE3F4 is a tetra-hydroquinoline and behaves as an uncompetitive. The second generation of Epac1 inhibitors named AM- is a subfamily of thieno[2,3-b]pyridine and functions both in vitro and in vivo. We are currently investigating the effect of AM- and CE3F4 in various experimental models of cardiac diseases to test the therapeutic ef-fectiveness of inhibiting Epac1 activity using small-molecule pharmacotherapy.

NANOPARTICLES AS NEW THERAPEUTICS IN HF

 

Yohan Santin, Maximin Détrait, Jessica Resta, Frank lezoualc’h

Numerous studies have shown that autophagy, a dynamic process by which damaged intracellular com-ponents are eliminated, is dysfunctional and plays an important role in the development of Heart Failure. Thus, an improvement in autophagy could counter the death of cardiac cells and protect the heart against contractile dysfunction. We are developing nanoparticles that aim at restoring autophagy by acting specifi-cally on lysosomes. Lysosomes are cellular structures that break down damaged material allowing its elimi-nation or recycling. We have shown a good efficiency of these nanoparticles to ameliorate autophagy, and protect cardiac cells from death induced by different stress agents. Our nanoparticles are currently being evaluated for their ability to limit the development of heart failure.

New epigenetic mechanisms in heart failure

 

Loubna Kehal, Dorian Bergonnier, Yannis Sainte-Marie, Olivier Lairez, Frank Lezoualc’h, Caroline Conte

Epigenetic markers have recently emerged as key players in the development of cardiovascular disease, suggesting that chromatin modifiers may represent promising targets for the development of new therapies. Cardiac hypertrophy, an early marker in the clinical course of heart failure, is regulated by various signalling pathways that activate a specific gene program characterized by the re-expression of certain fetal genes and repression of genes specific to mature cardiomyocytes. Although a specific epigenetic signature in hyper-trophic cardiomyocytes has been shown, the link between well-characterized signalling pathways and epi-genetic changes is still poorly understood. We have recently identified epigenetic enzymes that modify the histone methylation profiles in cardiomyocytes during cardiac stress. We are trying to understand the impact of these enzymes on gene regulation and the mechanisms regulating their activity and/or recruitment to their target genes in response to cardiac stress.

Selected publications


Mitochondrial 4-HNE derived from MAO-A promotes mitoCa2+ overload in chronic post-ischemic cardiac remodelling.  
Santin Y, Fazal L, Sainte-Marie Y, Sicard P, Maggiorani D, Tortosa F, Yücel Yücel Y, Teyssedre L, Rouquette J, Marcellin M, Vindis C, Shih JC, Lairez O, Burlet-Schiltz O, Parini A, Lezoualc’h F and Mialet-Perez J.
. Cell Death and Differentiation (2020).
. Pubmed

Rational re-design of Monoamine Oxidase A into a dehydrogenase to probe ROS in cardiac ageing. 
Giacinto Iacovino L, Manzella N, Resta J, Vanoni MA, Rotilio Laura, Pisani L, Edmondson DE, Pa-rini A, Mattevi A, Mialet-Perez J, Binda C.
ACS Chem Biol (2020) . Pubmed

Identification of a pharmacological inhibitor of Epac1 that protects the heart against acute and chronic models of cardiac stress. .
Laudette M, Coluccia A, Sainte-Marie Y, Solari A, Fazal L, Sicard P, Silvestri R, Mialet-Perez J, Pons S, Ghaleh B, Blondeau JP, Lezoualc’h F.
Cardiovasc Res. (2019). Pubmed

Monoamine oxidase-A is a novel driver of stress-induced premature senescence through inhibi-tion of parkin-mediated mitophagy.
Manzella N, Santin Y, Maggiorani D, Martini H, Douin-Echinard V, Passos JF, Lezoualc’h F, Binda C, Parini A and Mialet-Perez J.
. Aging Cell (2018). .
Pubmed

The multifunctional mitochondrial Epac1 controls myocardial cell death
Fazal L, Laudette M, Paula-Gomes S, Pons S, Conte C, Tortosa F, Sicard P, Sainte-Marie Y, Bis-serier M, Lairez O, Lucas A, Roy J, Ghaleh B, Fauconnier J, Mialet-Perez J, Lezoualc’h F.
Circ Res (2017) . Pubmed

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