TEAM F. Lezoualch / J. Mialet

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

Researcher

Jeanne MIALET-PEREZ

Associate profesor

Caroline CONTE

Associate profesor

Yannis SAINTE-MARIE

Bertrand MARCHEIX
Clinician

Bertrand MARCHEIX

Clinician

Clément DELMAS

Olivier LAIREZ
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

Dorian BERGONNIER
Engineer

Dorian BERGONNIER

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.

Researcher

Jeanne MIALET-PEREZ

INSERM researcher

Jeanne Mialet-Perez is working in the field of cardiac aging and age-associated diseases. She is specialized in the effects of oxidative stress-mediated signaling pathways of cardiomyocytes such as autophagy, apoptosis and senescence. She contributed to a better understanding of the role of mitochondrial enzymes monoamine oxidases in cardiac diseases.

Career path
Jeanne Mialet-Perez received her PhD in Endocrinology at the University of Paris, France, in 2002. After a post-doctoral experience at the University of Cincinnati, (Ohio, USA) in 2002-2005 in “genetic of cardiovascular diseases”, she joined the institute I2MC of Toulouse where she was recruited as a research associate at INSERM.

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

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.

Associate profesor

Yannis SAINTE-MARIE

Associate Professor in physiology at the Faculty of Pharmaceuticals sciences, Toulouse

Yannis Sainte-Marie is involved in the characterization of the target identified in the team at the level of their functional impact in preclinical model of heart pathologies such as aortic stenosis, myocardial infartion, diabetic cardiomyopathy.

Career path
Yannis Sainte-Marie has a PhD in Biology from the Paris VII University, France, in 2006 for his work on new roles for the mineralocorticoid receptor in physiopathology. After a post-doctoral project on molecular actor of heart failure, he was recruited as assistant professor in Physiology at the Faculty of Pharmaceuticals sciences and joined the team in 2010.

Main domains of expertise
Cardiac physiopathology, animal model design and phenotypic characterization.

Clinician

Bertrand MARCHEIX

Clinician

Clément DELMAS

Clinician

Olivier LAIREZ

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.

Cheminement de carrière
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.

Domaine d’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.

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, Jeanne Mialet-Perez

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

ILS NOUS SOUTIENNENT

logotype i2mc
logotype i2mc

Inserm/UPS UMR 1297 - I2MC Institut des Maladies Métaboliques et Cardiovasculaires

1 avenue Jean Poulhès - BP 84225 - 31432 Toulouse Cedex 4

Tél. : 05 61 32 56 00

Contactez-nous

 

Horaires

Du lundi au vendredi
8h30 - 12h30 / 13h45 -16h45