Thesis defense Marine Sallé

Equipe

Team I - Human Genetics

Directeur de thèse

Encadrant

Romain Capoulade

Rapporteurs

Sylvain Fraineau, PhD,  INSERM U1096, Université de Rouen Normandie
Mathilde Varre, PhD,  INSERM U1148  

Examinatrice

Abstract

Biological prosthesis implantation is the main solution for calcific aortic valve stenosis patients, however their limited durability remains a major concern. Clinical studies highlighted an association between circulating lipidic factors (PCSK9, lipoprotein(a), LDL-cholesterol) and bioprostheses degeneration, but the underlying mechanisms are still unknown. Therefore, I studied hypercholesterolemia and PCSK9 role in the context of early bioprostheses degeneration (SVD).

The analysis of prosthetic patches implanted subcutaneously, in genetically modified mice, highlighted the activation of inflammation, mainly mediated by macrophages, and the activation of fibro-calcific remodeling of the tissues in hypercholesterolemic and high PCSK9 conditions. In vitro investigation of cellular mechanisms suggested the implication of the oxidized LDL and PCSK9 in inflammation activation whereas only PCSK9 seemed to contribute to fibro-calcific remodeling.

Since this model was not physiological, my team developed a model of orthotopic valve replacement in Yucatan minipigs. Preliminary histological and transcriptomic data allowed to better understand SVD early mechanisms. This model will be useful to validate our results on hypercholesterolemia and PCSK9 involvement in SVD.

This work supports the implication of the lipidic factors in SVD and suggest that they might be involved in the inflammatory and calcifying processes observed in the bioprostheses.