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Eur J Pharmacol. 2014 Jan 15;723:322-9. doi: 10.1016/j.ejphar.2013.11.009. Epub 2013 Nov 22.

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

Author information

1
Department of Pharmacology, School of Medicine, University of California at Irvine, Irvine, CA 92697-4625 USA.
2
Department of Pharmacology, School of Medicine, University of California at Irvine, Irvine, CA 92697-4625 USA. Electronic address: dnkrause@uci.edu.

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 17β-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-γ coactivator-1 alpha (PGC-1α) but increased levels of the other PGC-1 isoforms: PGC-1β and PGC-1 related coactivator (PRC). In vessels ex vivo, estrogen decreased protein levels of PGC-1α via activation of phosphatidylinositol 3-kinase (PI3K). Estrogen treatment also increased phosphorylation of forkhead transcription factor, FoxO1, a known pathway for PGC-1α downregulation. In contrast to the decrease in PGC-1α, 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-1β 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-1β, 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-1β and/or PRC, estrogen appears to enhance mitochondrial biogenesis, function and reactive oxygen species protection.

KEYWORDS:

Cerebral blood vessels; Estrogen; Glutamate-cysteine ligase; Glutathione; Mitochondria; Peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1)

PMID:
24275351
PMCID:
PMC4028038
DOI:
10.1016/j.ejphar.2013.11.009
[Indexed for MEDLINE]
Free PMC Article
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