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Abstract :
[en] Primary mitral regurgitation (MR), due to valve prolapse, is one of the most frequent valvular heart diseases affecting around 2.5% of the population. Primary mitral regurgitation is becoming increasingly more prevalent as a result of population aging. In its most severe form, it may lead to pressure overload and heart failure with poor outcomes and about 2% of sudden death. As there is no blood biomarker available in clinical laboratories for its diagnosis, observation of clinical manifestations and echocardiography measurements constitute the current management of patients. Moreover, the molecular deregulation leading to myxomatous degeneration and mitral valve prolapse remains largely unknown.
In the present work, we used a targeted and a non-targeted proteomic approach in order to identify biomarkers for the diagnosis of primary mitral regurgitation. Moreover, we brought out potential biological processes altered in the pathology. We identified 7 differentially expressed proteins between patients with or without mitral regurgitation. Differential protein levels between groups indicated a decrease in the reverse cholesterol transport, a potential oxidative stress and a haemolytic state as well as impairment in cell proliferation and apoptosis. In addition, we found an increase of autophagy activity in myxomatous mitral valves compared to healthy mitral valves.
In a second part of the work, we investigated the molecular regulation of the autophagy pathway. C16-ceramide treatment allowed us to induce autophagic cell death in HCT116 cells. We found that C16-ceramide induced the phosphorylation of emerin, a nuclear membrane protein, at its LEM domain. Moreover, we highlighted that this phosphorylation was required for the induction of autophagy by emerin. Moreover, we found a direct interaction between emerin and LC3, the marker of autophagosome formation. To go further in deciphering the role of emerin in the C16-ceramide autophagy pathway, we identified new binding partners through biochemical purification and mass spectrometry analysis.