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Nouvelles cibles pharmacologiques du traitement de la dysfonction cardiovasculaire associée au syndrome métabolique

Abstract : Metabolic Syndrome (MS) is associated with an increase in cardiovascular adverse events and specifically with heart failure with preserved ejection fraction (HFpEF). HFpEF represents up to 50% of HF however, no treatment effective on mortality has been yet identified. MS related-HFpEF is a multifactorial syndrome in which an increase in endothelin signaling, in mineralocorticoid receptor activation as well as mitochondria dysfunction is found and participate to the pathology. The present goal of the thesis was to evaluate in three different projects the effects of short- (1 week) and long-term (3 months) treatments, each targeting one of these biological systems, on cardiovascular dysfunction observed in a rat model of MS associated HFpEF. We have chosen the endothelin receptors antagonist macitentan, the mineralocorticoid receptor antagonist finerenone and the new glucose-lowering agent imeglimin. Our results clearly show after the short-term studies an improvement in diastolic dysfunction, an increase in myocardial perfusion as well as restoration of endothelium-dependent coronary relaxation with the 3 treatments. All these improvements were associated with a decrease in left ventricular (LV) reactive oxygen species production (ROS). We obtained the same results after the long-term studies with a decrease in LV interstitial collagen deposition. ROS production was also decreased with the 3 components. This study clearly shows that in a rat model of MS related-HFpEF, blocking endothelin receptors or mineralocorticoid receptors as well as preventing mitochondrial dysfunction is associated with an improvement in cardiac and vascular dysfunctions. These improvements probably involve, among other mechanisms, a decrease in oxidative stress.
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Submitted on : Friday, May 15, 2020 - 10:40:46 AM
Last modification on : Friday, October 23, 2020 - 5:04:30 PM

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  • HAL Id : tel-02569400, version 2

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Marianne Lachaux. Nouvelles cibles pharmacologiques du traitement de la dysfonction cardiovasculaire associée au syndrome métabolique. Sciences pharmaceutiques. Normandie Université, 2019. Français. ⟨NNT : 2019NORMR010⟩. ⟨tel-02569400v2⟩

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