Rôle protecteur de l'estradiol contre les conséquences systémiques et cellulaires dans un modèle d'apnées obstructives du sommeil : implication des récepteurs nucléaires ERa et ERB
|Advisor:||Joseph, Vincent; Roussel, Damien; Bairam, Aida|
|Abstract:||Sleep apnea (SA) induces constant changes of arterial oxygenation (Intermittent hypoxia - IH) that affect about 5 to 7% of the general population. IH increases oxidative stress (production of reactive oxygen species – ROS) and lead to cardiovascular, neurological and metabolic risks. Epidemiological studies show that the prevalence of SA is lower in women than in men, but after menopause the prevalence increases to the same level that in men. Estradiol (E2) is a potent antioxidant, but its potential role in the treatment or prevention of SA is not exploited. However, estradiol (with or without progesterone) can reduce SA in postmenopausal women. ROS can be produced by mitochondria, NADPH oxidase and/or Xanthine oxidase. Mitochondria is the most important producer of ROS (90% of oxygen consumed) and its dysfunction is very detrimental. Estradiol is a target of mitochondria through its mitochondria alpha and beta (ERa et ERβ) that are able to modulate mitochondrial function and decrease ROS production. We tested the hypothesis in ovariectomized animal model exposed to IH, that estradiol and its specific receptor ERa and ERβ agonists are able to limit cerebral oxidative stress, mitochondrial dysfunction and the appearance of systemic disorders Our results have shown that estradiol is able to avoid the increase of blood pressure and the occurrence of respiratory disorders caused by IH. Furthermore, IH increases cerebral oxidative stress by increasing activity of pro-oxidant enzymes and decreasing activity of antioxidant enzymes. Estradiol prevents against the increase of oxidative stress. There is also a mitochondrial respiratory chain dysfunction in the cortex by IH, that is preserved differently by treatment with selective ERa and ERβ receptor modulators (SERMs). We have shown that ERβ plays an important role in cardiorespiratory control and mitochondrial function in the brain. Our results provide a better understanding of the role of estradiol as a protective agent against sleep apnea and its associated consequences. The use of specific agonists informs us on the role of each receptors in estradiol-induced protection against mitochondrial dysfunction. The use of hormone replacement with estradiol or SERMs may be an effective therapy against sleep apnea and its consequences.|
|Document Type:||Thèse de doctorat|
|Open Access Date:||18 April 2019|
|Collection:||Thèses et mémoires|
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