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Rôle de SIRT1 et de la biogenèse mitochondriale dans la prolifération des cellules du muscle lisse de l'artère pulmonaire

Abstract : Pulmonary arterial hypertension (PAH) is a lethal disease characterized by an intensive vascular remodelling, mainly due to hyper-proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs). Recently it has been found that PASMCs, similarly to cancer cells, demonstrate a shift in energy metabolism from oxidative phosphorylation towards glycolysis thus contributing to their particular phenotype. The deacetylase sirtuin1 (SIRT1) is an important modulator of energy metabolism, particularly via its activation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), the master regulator of mitochondrial biogenesis. Here we show for the first time that rat and human PASMC proliferation is characterised by a diminution of SIRT1 activity, and is potentiated by SIRT1 pharmacological inhibition or specific downregulation. Moreover, after chronic hypoxia exposure, SIRT1 KO mice display a more intense vascular remodelling compared to their control littermates and this is associated with an exacerbated increase in right ventricle systolic pressure and hypertrophy. Conversely, pharmacological SIRT1 activation strongly inhibits PASMC proliferation, and is associated with the activation of mitochondrial biogenesis. In general, the data obtained show that SIRT1 inactivation plays a causative role in PASMC proliferation and this enzyme could be a promising therapeutic target for PAH treatment.
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https://theses.hal.science/tel-01557235
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Submitted on : Thursday, July 6, 2017 - 3:02:51 AM
Last modification on : Tuesday, October 18, 2022 - 3:31:42 AM
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  • HAL Id : tel-01557235, version 1

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Giada Zurlo. Rôle de SIRT1 et de la biogenèse mitochondriale dans la prolifération des cellules du muscle lisse de l'artère pulmonaire. Biologie moléculaire. Université Paris Saclay (COmUE), 2015. Français. ⟨NNT : 2015SACLS205⟩. ⟨tel-01557235⟩

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