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Rôle de PGC-1α dans le système cardiovasculaire : recherche d’activateurs cœur-spécifiques et étude de ses mécanismes de régulation dans le muscle lisse aortique

Abstract : Heart failure (HF) is still the major cause of morbimortality in industrialized countries that justify the research of new treatments. Characterized in part by metabolic disorders including mitochondrial dysfunction, energetic metabolism appears as an essential component in HF development. These last years, PGC-1α has been proposed as a central actor of mitochondrial function control and thus as a therapeutic target of interest.The development of a cellular robotized assay in cardiac-like differentiated H9c2 cells allowed identification of three families: steroid hormones, B vitamins and fatty acids, able to induce the expression of PGC-1α and thus up-regulate mitochondrial biogenesis and mitochondrial respiration. The validation of these effects in adult rat cardiomyocytes lets in the one hand to validate the suitability of the assay and in the other hand to confirm that PGC-1α induction leads to mitochondrial biogenesis activation. Consequently, this assay constitutes a major asset to find new activators of PGC-1α to better understand its regulation in heart and provides interesting perspectives for the research of therapeutic pharmacologic compounds.Mechanisms controlling mitochondrial biogenesis in response to hypertension in vascular smooth muscle remain unclear. In this context, the second part of this work was to identify how mitochondrial biogenesis is modulated in arterial hypertension. Using an experimental model of hypertension and after validation in cultivated smooth muscle cells, we show a mitochondrial biogenesis induction in response to hypertension in relation with an increase in oxidative stress. Moreover, this induction is associated with a significant increase in CaMKII activity which was totally blocked by an antioxidant: resveratrol. These results suggest a regulation of mitochondrial biogenesis by oxidative stress via a CaMKII mechanism in vascular smooth muscle.
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Matthieu Ruiz. Rôle de PGC-1α dans le système cardiovasculaire : recherche d’activateurs cœur-spécifiques et étude de ses mécanismes de régulation dans le muscle lisse aortique. Sciences agricoles. Université Paris Sud - Paris XI, 2012. Français. ⟨NNT : 2012PA114830⟩. ⟨tel-00834420⟩

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