title: Aging negatively affects estrogens-mediated effects on nitric oxide bioavailability by shifting ERα/ERβ balance in female mice.
abstract: OBJECTIVE
  Aging is among the major causes for the lack of cardiovascular protection by estrogen (E2) during postmenopause. Our study aims to determine the mechanisms whereby aging changes E2 effects on nitric oxide (NO) production in a mouse model of accelerated senescence (SAM).
  
  
  RESULTS
  Although we found no differences on NO production in females SAM prone (SAMP, aged) compared to SAM resistant (SAMR, young), by either DAF-2 fluorescence or plasmatic nitrite/nitrate (NO2/NO3), in both cases, E2 treatment increased NO production in SAMR but had no effect in SAMP. Those results are in agreement with changes of eNOS protein and gene expression. E2 up-regulated eNOS expression in SAMR but not in SAMP. E2 is also known to increase NO by decreasing its catabolism by superoxide anion (O(2)(-)). Interestingly, E2 treatment decreased O(2)(-) production in young females, while increased O(2)(-) in aged ones. Furthermore, we observed that aging changed expression ratio of estrogen receptors (ERβ/ERα) and levels of DNA methylation. Increased ratio ERβ/ERα in aged females is associated to a lack of estrogen modulation of NO production and with a reversal in its antioxidant effect to a pro-oxidant profile.
  
  
  CONCLUSIONS
  Together, our data suggest that aging has detrimental effects on E2-mediated benefits on NO bioavailability, partially by affecting the ability of E2 to induce up regulation of eNOS and decrease of O(2)(-). These modifications may be associated to aging-mediated modifications on global DNA methylation status, but not to a specific methylation at 5'flanking region of ERα gene.
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Novensà
authors.forename: Susana
authors.initials: S
authors.lastname: Novella
authors.forename: Pascual
authors.initials: P
authors.lastname: Medina
authors.forename: Gloria
authors.initials: G
authors.lastname: Segarra
authors.forename: Nadia
authors.initials: N
authors.lastname: Castillo
authors.forename: Magda
authors.initials: M
authors.lastname: Heras
authors.forename: Carlos
authors.initials: C
authors.lastname: Hermenegildo
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Dantas
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D019175:DNA Methylation / Q000187:drug effects; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005455:Fluorescent Antibody Technique; D051379:Mice; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*
chemical_list: D004967:Estrogens; D011960:Receptors, Estrogen; D009569:Nitric Oxide; D019255:NADPH Oxidases