title: Impaired transcriptional activity of Nrf2 in age-related myocardial oxidative stress is reversible by moderate exercise training.
abstract: Aging promotes accumulation of reactive oxygen/nitrogen species (ROS/RNS) in cardiomyocytes, which leads to contractile dysfunction and cardiac abnormalities. These changes may contribute to increased cardiovascular disease in the elderly. Inducible antioxidant pathways are regulated by nuclear erythroid 2 p45-related factor 2 (Nrf2) through antioxidant response cis-elements (AREs) and are impaired in the aging heart. Whereas acute exercise stress (AES) activates Nrf2 signaling and promotes myocardial antioxidant function in young mice (~2 months), aging mouse (>23 months) hearts exhibit significant oxidative stress as compared to those of the young. The purpose of this study was to investigate age-dependent regulation of Nrf2-antioxidant mechanisms and redox homeostasis in mouse hearts and the impact of exercise. Old mice were highly susceptible to oxidative stress following high endurance exercise stress (EES), but demonstrated increased adaptive redox homeostasis after moderate exercise training (MET; 10m/min, for 45 min/day) for ~6 weeks. Following EES, transcription and protein levels for most of the ARE-antioxidants were increased in young mice but their induction was blunted in aging mice. In contrast, 6-weeks of chronic MET promoted nuclear levels of Nrf2 along with its target antioxidants in the aging heart to near normal levels as seen in young mice. These observations suggest that enhancing Nrf2 function and endogenous cytoprotective mechanisms by MET, may combat age-induced ROS/RNS and protect the myocardium from oxidative stress diseases.
authors.affiliation: Divisions of Cardiology and Pulmonary, Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA.
authors.forename: Sellamuthu S
authors.initials: SS
authors.lastname: Gounder
authors.forename: Sankaranarayanan
authors.initials: S
authors.lastname: Kannan
authors.forename: Dinesh
authors.initials: D
authors.lastname: Devadoss
authors.forename: Corey J
authors.initials: CJ
authors.lastname: Miller
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Whitehead
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Whitehead
authors.forename: Shannon J
authors.initials: SJ
authors.lastname: Odelberg
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Firpo
authors.forename: Robert
authors.initials: R
authors.lastname: Paine
authors.forename: John R
authors.initials: JR
authors.lastname: Hoidal
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.forename: Namakkal S
authors.initials: NS
authors.lastname: Rajasekaran
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004578:Electron Spin Resonance Spectroscopy; D005456:Fluorescent Dyes; D005978:Glutathione / Q000378:metabolism; D006706:Homeostasis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010805:Physical Conditioning, Animal; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D005456:Fluorescent Dyes; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D005978:Glutathione