title: 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 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.
authors.affiliation: Department of Pharmacology, School of Medicine, University of California at Irvine, Irvine, CA 92697-4625 USA.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Kemper
authors.affiliation: Department of Pharmacology, School of Medicine, University of California at Irvine, Irvine, CA 92697-4625 USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Stirone
authors.affiliation: Department of Pharmacology, School of Medicine, University of California at Irvine, Irvine, CA 92697-4625 USA. Electronic address: dnkrause@uci.edu.
authors.forename: Diana N
authors.initials: DN
authors.lastname: Krause
authors.affiliation: Department of Pharmacology, School of Medicine, University of California at Irvine, Irvine, CA 92697-4625 USA.
authors.forename: Sue P
authors.initials: SP
authors.lastname: Duckles
authors.affiliation: Department of Pharmacology, School of Medicine, University of California at Irvine, Irvine, CA 92697-4625 USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Procaccio
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D023281:Genomics; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051265:NF-E2-Related Factor 1 / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010052:Ovariectomy; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D000071161:Forkhead Box Protein O1
chemical_list: D000255:Adenosine Triphosphate; D004958:Estradiol; D004967:Estrogens; D051858:Forkhead Transcription Factors; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D051265:NF-E2-Related Factor 1; D009419:Nerve Tissue Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020033:Protein Isoforms; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C501429:Ppargc1a protein, rat; C489030:Tfam protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1
keywords: Cerebral blood vessels; Estrogen; Glutamate-cysteine ligase; Glutathione; Mitochondria; Peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1)