Thesis defense Martin Bouaud

Equipe

Team II - Ion channels and cardiopathies

Directeur de thèse 

Benjamin Lauzier

Co-directrice

Aurélia Leroux

Rapporteurs

Tarik Issad, PhD, Directeur de recherche, Institut Cochin, Inserm U1016, CNRS UMR 104, Université de Paris, Paris
Magali Théveniau-Ruissy, PhD, Chargée de recherche, Marseille Medical Genetics, UMR 1251, Aix-Marseille Université, Marseille

Examinateurs

Mélanie Paillard, PhD, Chargée de recherche,  Laboratoire CarMeN, INSERM U1060, INRAE U1397, Université Lyon1, Lyon
Daan Van Aalten, PhD, Professor, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
 

Abstract 

 Congenital heart disease (CHD) is the most common congenital malformation. Cardiac development relies on a tight regulation of morphogenetic, metabolic and signaling events that ensure the maturation of a functional myocardium. Among the metabolic pathways involved in this process, the hexosamine biosynthetic pathway and its end-product UDP-GlcNAc, sugar donor for protein O-GlcNAcylation, have emerged as important regulators of cellular homeostasis. Although O-GlcNAcylation has been implicated in numerous physiological and pathological processes, its role during cardiac development remain poorly understood.

The first objective of our work was to investigate the consequences of a chronic increase in protein O-GlcNAcylation during cardiac development. Pregnant rats were treated daily with an O-GlcNAcase inhibitor, NButGT, throughout embryogenesis, to induce sustained elevation of O-GlcNAcylation in the developing embryo. Cardiac morphology, cardiomyocyte proliferation, myocardial maturation and molecular signaling pathways were subsequently analyzed in the offspring to determine how increased protein O-GlcNAcylation affects normal heart development. Treatment with NButGT increased O-GlcNAcylation levels in embryo’s heart, associated with increased heart-to-embryo weight ratio, indicating heart hypertrophy. Hearts displayed a delay in ventricular compaction, and both septal and ventricular thickening. Transcriptome and O-GlcNAcome analyses identified targets involved in cell growth, cell proliferation and metabolism.

The second part of our work focused on cyanotic congenital heart disease. Children with severe cyanotic heart defects are exposed to chronic hypoxia for months or years before surgical repair while maintaining a surprisingly preserved cardiac function. The molecular mechanisms underlying this remarkable adaptation remain incompletely understood. Clinical data were examined to evaluate the impact of chronic hypoxia on postoperative outcomes. Unexpectedly, chronic hypoxia was not associated with poorer postoperative outcomes and was even associated with lower postoperative organ dysfunction scores, supporting the existence of adaptive mechanisms in the chronically hypoxic pediatric heart. Myocardial samples from cyanotic and acyanotic patients undergoing corrective surgery were analyzed using biochemical and proteomic approaches. Proteomic and biochemical analyses revealed alterations in metabolic pathways, associated with perturbations of several other signaling pathways in cyanotic myocardium.

Overall, our work identifies O-GlcNAcylation as an important regulator of cardiac development These findings improve our understanding of the metabolic and signaling pathways involved in cardiac maturation. This opens new perspectives for myocardial protection in cyanotic congenital heart disease.