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Genomic and non-genomic regulation of PGC1 isoforms by estrogen to increase cerebral vascular mitochondrial biogenesis and reactive oxygen species protection

Abstract :

We previously found that estrogen exerts a novel protective effect on mitochondria in brain vasculature. Here we demonstrate in rat cerebral blood vessels that 17beta-estradiol (estrogen), both in vivo and ex vivo, affects key transcriptional coactivators responsible for mitochondrial regulation. Treatment of ovariectomized rats with estrogen in vivo lowered mRNA levels of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1alpha) but increased levels of the other PGC-1 isoforms: PGC-1beta and PGC-1 related coactivator (PRC). In vessels ex vivo, estrogen decreased protein levels of PGC-1alpha via activation of phosphatidylinositol 3-kinase (PI3K). Estrogen treatment also increased phosphorylation of forkhead transcription factor, FoxO1, a known pathway for PGC-1alpha downregulation. In contrast to the decrease in PGC-1alpha, estrogen increased protein levels of nuclear respiratory factor 1, a known PGC target and mediator of mitochondrial biogenesis. The latter effect of estrogen was independent of PI3K, suggesting a separate mechanism consistent with increased expression of PGC-1beta and PRC. We demonstrated increased mitochondrial biogenesis following estrogen treatment in vivo; cerebrovascular levels of mitochondrial transcription factor A and electron transport chain subunits as well as the mitochondrial/nuclear DNA ratio were increased. We examined a downstream target of PGC-1beta, glutamate-cysteine ligase (GCL), the rate-limiting enzyme for glutathione synthesis. In vivo estrogen increased protein levels of both GCL subunits and total glutathione levels. Together these data show estrogen differentially regulates PGC-1 isoforms in brain vasculature, underscoring the importance of these coactivators in adapting mitochondria in specific tissues. By upregulating PGC-1beta and/or PRC, estrogen appears to enhance mitochondrial biogenesis, function and reactive oxygen species protection.

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https://hal.univ-angers.fr/hal-03403993
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Soumis le : mardi 26 octobre 2021 - 14:02:25
Dernière modification le : mardi 12 avril 2022 - 18:22:05

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M. Kemper, C. Stirone, D. Krause, S. Duckles, Vincent Procaccio. Genomic and non-genomic regulation of PGC1 isoforms by estrogen to increase cerebral vascular mitochondrial biogenesis and reactive oxygen species protection. European Journal of Pharmacology, Elsevier, 2014, 723, pp.322 - 9. ⟨10.1016/j.ejphar.2013.11.009⟩. ⟨hal-03403993⟩

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