title: 17β-Estradiol, aging, inflammation, and the stress response in the female heart.
abstract: Heat shock proteins (HSPs) are a cardioprotective class of proteins induced by stress and regulated by the transcription factor, heat shock factor (HSF)-1. 17β-estradiol (E(2)) indirectly regulates HSP expression through rapid activation of nuclear factor-κB (NF-κB) and HSF-1 and protects against hypoxia. As males experience a loss of protective cellular responses in aging, we hypothesized that aged menopausal (old ovariectomized) rats would have an impaired HSP response, which could be prevented by immediate in vivo E(2) replacement. After measuring cardiac function in vivo, cardiac myocytes were isolated from ovariectomized adult and old rats with and without 9 weeks of E(2) replacement. Myocytes were treated with E(2) in vitro and analyzed for activation of NF-κB, HSF-1, and HSP expression. In addition, we measured inflammatory cytokine expression and susceptibility to hypoxia/reoxygenation injury. Cardiac contractility was reduced in old ovariectomized rats and could prevented by immediate E(2) replacement in vivo. Subsequent investigations in isolated cardiac myocytes found that in vitro E(2) activated NF-κB, HSF-1, and increased HSP 72 expression in adult but not old rats. In response to hypoxia/reoxygenation, myocytes from adult, but not old, rats had increased HSP 72 expression. In addition, expression of the inflammatory cytokines TNF-α and IL-1β, as well as oxidative stress, were increased in myocytes from old ovariectomized rats; only the change in cytokine expression could be attenuated by in vivo E(2) replacement. This study demonstrates that while aging in female rats led to a loss of the cardioprotective HSP response, E(2) retains its protective cellular properties.
authors.affiliation: Molecular and Cellular Cardiology, Genomics and Biomedical Sciences Facility, Room 6317, University of California, Davis, 451 Health Sciences Way, Davis, California 95616, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Stice
authors.forename: Le
authors.initials: L
authors.lastname: Chen
authors.forename: Se-Chan
authors.initials: SC
authors.lastname: Kim
authors.forename: J S
authors.initials: JS
authors.lastname: Jung
authors.forename: A L
authors.initials: AL
authors.lastname: Tran
authors.forename: T T
authors.initials: TT
authors.lastname: Liu
authors.forename: Anne A
authors.initials: AA
authors.lastname: Knowlton
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004452:Echocardiography; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology*; D000076249:Heat Shock Transcription Factors; D007249:Inflammation / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010052:Ovariectomy; D016133:Polymerase Chain Reaction; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D004958:Estradiol