Impaired Transcriptional Activity of Nrf2 in Age-Related Myocardial Oxidative Stress Is Reversible by Moderate Exercise Training
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{"title"=>"Impaired Transcriptional Activity of Nrf2 in Age-Related Myocardial Oxidative Stress Is Reversible by Moderate Exercise Training", "type"=>"journal", "authors"=>[{"first_name"=>"Sellamuthu S.", "last_name"=>"Gounder", "scopus_author_id"=>"54408381800"}, {"first_name"=>"Sankaranarayanan", "last_name"=>"Kannan", "scopus_author_id"=>"14630650100"}, {"first_name"=>"Dinesh", "last_name"=>"Devadoss", "scopus_author_id"=>"55365159400"}, {"first_name"=>"Corey J.", "last_name"=>"Miller", "scopus_author_id"=>"7406256007"}, {"first_name"=>"Kevin S.", "last_name"=>"Whitehead", "scopus_author_id"=>"35286279800"}, {"first_name"=>"Shannon J.", "last_name"=>"Odelberg", "scopus_author_id"=>"6701561641"}, {"first_name"=>"Matthew A.", "last_name"=>"Firpo", "scopus_author_id"=>"7003456588"}, {"first_name"=>"Robert", "last_name"=>"Paine", "scopus_author_id"=>"7102460664"}, {"first_name"=>"John R.", "last_name"=>"Hoidal", "scopus_author_id"=>"7004761665"}, {"first_name"=>"E. Dale", "last_name"=>"Abel", "scopus_author_id"=>"7202417444"}, {"first_name"=>"Namakkal S.", "last_name"=>"Rajasekaran", "scopus_author_id"=>"6603650460"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-84866645959", "pmid"=>"23029187", "sgr"=>"84866645959", "doi"=>"10.1371/journal.pone.0045697", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "issn"=>"19326203", "pui"=>"365720534"}, "id"=>"752fc4be-83d0-33a9-8ade-132903f2d304", "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.", "link"=>"http://www.mendeley.com/research/impaired-transcriptional-activity-nrf2-agerelated-myocardial-oxidative-stress-reversible-moderate-ex", "reader_count"=>57, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>5, "Researcher"=>12, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>9, "Student > Postgraduate"=>1, "Other"=>3, "Student > Master"=>9, "Student > Bachelor"=>9, "Lecturer"=>1, "Professor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>5, "Researcher"=>12, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>9, "Student > Postgraduate"=>1, "Other"=>3, "Student > Master"=>9, "Student > Bachelor"=>9, "Lecturer"=>1, "Professor"=>3}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>6, "Nursing and Health Professions"=>1, "Agricultural and Biological Sciences"=>30, "Medicine and Dentistry"=>10, "Neuroscience"=>1, "Veterinary Science and Veterinary Medicine"=>1, "Sports and Recreations"=>2, "Psychology"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>10}, "Neuroscience"=>{"Neuroscience"=>1}, "Sports and Recreations"=>{"Sports and Recreations"=>2}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>30}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>6}, "Unspecified"=>{"Unspecified"=>3}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "Veterinary Science and Veterinary Medicine"=>{"Veterinary Science and Veterinary Medicine"=>1}}, "reader_count_by_country"=>{"United States"=>1, "Japan"=>1, "Mexico"=>1, "Germany"=>1, "Indonesia"=>1, "Spain"=>1}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/571917"], "description"=>"<p>Proposed model for age-associated deregulation and exercise training mediated stabilization of Nrf2/ARE-signaling.</p>", "links"=>[], "tags"=>["age-associated", "deregulation", "mediated", "stabilization"], "article_id"=>242406, "categories"=>["Physiology", "Biochemistry", "Genetics"], "users"=>["Sellamuthu S. Gounder", "Sankaranarayanan Kannan", "Dinesh Devadoss", "Corey J. Miller", "Kevin S. Whitehead", "Shannon J. Odelberg", "Matthew A. Firpo", "Robert Paine III", "John R. Hoidal", "E. Dale Abel", "Namakkal S. Rajasekaran"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045697.g008", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Proposed_model_for_age_associated_deregulation_and_exercise_training_mediated_stabilization_of_Nrf2_ARE_signaling_/242406", "title"=>"Proposed model for age-associated deregulation and exercise training mediated stabilization of Nrf2/ARE-signaling.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 22:54:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/571637"], "description"=>"<p>Representative immunoblots of cytosolic extracts from the hearts of young and old mice under basal conditions and following 6-weeks of moderate exercise training (MET). Protein blots were probed with respective antibodies as indicated. Individual lanes represent separate animals (n = 4–6/group). A. Analysis of nuclear Nrf2 in young and old mice subjected to MET. In sedentary mice, Nrf2 protein levels were decreased significantly in old when compared to young (*p<0.05). Following MET, nuclear Nrf2 levels were significantly increased in old mice to levels equivalent to those of young mice (<b><sup>#, $</sup></b>p<0.05 in MET vs. respective basal). (B) Densitometry analysis of respective protein signals were performed using Image-J and expressed relative to mean values of the sedentary-young group. Under basal conditions, a significant decrease in the protein levels of GSR, G6PD, NQO1, catalase, GPX1 and GCS were observed in the heart tissues of old when compared to young mice. Following 6-weeks of moderate exercise, most of the antioxidants were significantly (*p<0.05) upregulated or stabilized in the aging heart.</p>", "links"=>[], "tags"=>["prolonged", "aging"], "article_id"=>242124, "categories"=>["Physiology", "Biochemistry", "Genetics"], "users"=>["Sellamuthu S. Gounder", "Sankaranarayanan Kannan", "Dinesh Devadoss", "Corey J. Miller", "Kevin S. Whitehead", "Shannon J. Odelberg", "Matthew A. Firpo", "Robert Paine III", "John R. Hoidal", "E. Dale Abel", "Namakkal S. Rajasekaran"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045697.g006", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_prolonged_moderate_exercise_on_Nrf2_ARE_Antioxidants_in_the_aging_heart_/242124", "title"=>"Effect of prolonged moderate exercise on Nrf2/ARE-Antioxidants in the aging heart.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 22:53:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/571220"], "description"=>"<p>Myocardial tissue sections (5 µm-thick) on slides were treated with cell-permeable fluorescent H<sub>2</sub>DCFDA (A) and DHE (B). The microscopic images were obtained at a magnification of 60X. The oxidized, fluorescent 2-hydroxyethidium and DCF was imaged using confocal microscopy and quantified using Simple PCI 6 Imaging Software. Increased superoxide and hydrogen peroxides were observed in old heart tissues under basal and EES conditions. Green-DCF, Red-DHE and Blue-DAPI (nucleus stain). Respective intensity calculations were shown in the bar-graphs. *p<0.001- between basal and EES; #p<0.001- between young and old.</p>", "links"=>[], "tags"=>["genetics and genomics", "physiology", "Biochemistry"], "article_id"=>241702, "categories"=>["Physiology", "Biochemistry", "Genetics"], "users"=>["Sellamuthu S. Gounder", "Sankaranarayanan Kannan", "Dinesh Devadoss", "Corey J. Miller", "Kevin S. Whitehead", "Shannon J. Odelberg", "Matthew A. Firpo", "Robert Paine III", "John R. Hoidal", "E. Dale Abel", "Namakkal S. Rajasekaran"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045697.g003", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_DCFDA_DHE_fluorescence_in_young_and_old_mice_/241702", "title"=>"DCFDA/DHE-fluorescence in young and old mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 22:50:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/571029"], "description"=>"<p>(<b>A</b>) <b>Decreased nuclear translocation of Nrf2 is evident in the heart of aging mice.</b> Representative immunoblot (IB) of nuclear proteins collected from young and aged WT mice (n = 6) under basal state. Each lane represents an individual animal/heart. Lamin-B1 used as loading control. Densitometry analysis of the IB images was achieved using Image-J. (<b>B</b>) <b>Transcription factor binding (TransAM-Nrf2 activity) assay:</b> Nuclear proteins from young and aged mice (n = 4) were incubated with the oligonucleotide (pre-coated on 96 well plate/strips) for ARE (antioxidant response element). (<b>C</b>) <b>Localization of Nrf2 by immunofluorescence:</b> Immunofluorescence analysis using anti-Nrf2-ab (1∶200; v/v) showing decreased cytosolic and nuclear Nrf2 in old versus young myocardium. Blue: nucleus (DAPI); Red: Nrf2-staining and Pink: merge of blue and red indicating nuclear localization of Nrf2. IF images were obtained at a magnification of 60X oil immersion. (<b>D</b>) <b>Glutathione redox-state:</b> Myocardial redox state was determined in the ventricles of 2 and 23 months old mice under basal conditions. Statistically significant changes in the redox ratio (GSH/GSSG) were observed in young and old groups. Values are mean ± SD for 5 or more animals in each group. (<b>E</b>) <b>Increased reactive oxygen species (ROS) generation in the hearts of aging mice:</b> Electron paramagnetic resonance (EPR) spectroscopy signals for CMH (1-hydroxy-3-methoxy-carbonyl-2, 2,5,5- tetramethyl pyrrolidine) in young and aged mice. EPR signals for CMH are significantly increased in aged versus young mouse myocardium. Values represent n = 5 or more from each group.</p>", "links"=>[], "tags"=>["nrf2", "aging"], "article_id"=>241505, "categories"=>["Physiology", "Biochemistry", "Genetics"], "users"=>["Sellamuthu S. Gounder", "Sankaranarayanan Kannan", "Dinesh Devadoss", "Corey J. Miller", "Kevin S. Whitehead", "Shannon J. Odelberg", "Matthew A. Firpo", "Robert Paine III", "John R. Hoidal", "E. Dale Abel", "Namakkal S. Rajasekaran"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045697.g001", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Decreased_function_of_Nrf2_in_the_aging_heart_/241505", "title"=>"Decreased function of Nrf2 in the aging heart.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 22:49:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/571496"], "description"=>"<p>A. Analysis of nuclear Nrf2 in young and old mice subjected to EES. In sedentary mice, Nrf2 protein levels were decreased significantly in young versus old mice. EES exacerbated the decrease of nuclear Nrf2 in old mice. Blots/values represent n = 4–6 from each group. *p<0.05 between young vs. old and <b><sup>#</sup></b>p<0.05-between basal vs. EES. (B) Representative immunoblots of cytosolic extracts from the hearts of young and old mice under basal conditions and following EES. Protein blots were probed with anti-HO1, NQO1, GCLM, GCLC, Catalase, SOD1, SOD2, GSR, G6PD, GPX1 and GAPDH. Individual lanes indicate a single animal. Densitometry analysis of respective protein signals was performed using Image-J and expressed as relative intensity units calculated as mean values of young and old, *p<0.05. Individual lanes indicate each animal (n = 6). <b><sup>#</sup></b>p<0.05-between basal and EES.</p>", "links"=>[], "tags"=>["analyses", "nrf2", "antioxidant"], "article_id"=>241980, "categories"=>["Physiology", "Biochemistry", "Genetics"], "users"=>["Sellamuthu S. Gounder", "Sankaranarayanan Kannan", "Dinesh Devadoss", "Corey J. Miller", "Kevin S. Whitehead", "Shannon J. Odelberg", "Matthew A. Firpo", "Robert Paine III", "John R. Hoidal", "E. Dale Abel", "Namakkal S. Rajasekaran"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045697.g005", "stats"=>{"downloads"=>4, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Immunoblot_analyses_of_protein_expression_for_Nrf2_and_antioxidant_enzymes_/241980", "title"=>"Immunoblot analyses of protein expression for Nrf2 and antioxidant enzymes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 22:52:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/571359"], "description"=>"<p>Real-time qPCR analyses for antioxidants were performed using Qiagen primer sets. Data were initially normalized to Arbp1 and then to the corresponding gene expression in the sedentary-young group. (n = 4–6). *p<0.05-between basal and EES.</p>", "links"=>[], "tags"=>["antioxidant", "genes"], "article_id"=>241847, "categories"=>["Physiology", "Biochemistry", "Genetics"], "users"=>["Sellamuthu S. Gounder", "Sankaranarayanan Kannan", "Dinesh Devadoss", "Corey J. Miller", "Kevin S. Whitehead", "Shannon J. Odelberg", "Matthew A. Firpo", "Robert Paine III", "John R. Hoidal", "E. Dale Abel", "Namakkal S. Rajasekaran"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045697.g004", "stats"=>{"downloads"=>3, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Transcription_of_Nrf2_ARE_dependent_antioxidant_genes_in_the_heart_/241847", "title"=>"Transcription of Nrf2/ARE-dependent antioxidant genes in the heart.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 22:51:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/571782"], "description"=>"<p>Immunofluorescence (IF) analysis using anti-Nrf2-ab (1∶200; v/v) showing nuclear translocation of Nrf2 in the hearts of young and old after MET (panel 1). Blue: nucleus (DAPI); Red: Nrf2-staining and Pink: merge of blue and red indicating nuclear localization of Nrf2. Panels 2–4 depict the expression of NQO1 (1∶400), HO1 (1∶150) and GSR (1∶200) in the cardiomyocytes of young and old mice after MET. The levels of these antioxidants were comparable in the cytosol of young and old (*p<0.05) cardiomyocytes after 6-weeks of exercise training. <b><sup>#</sup></b>p<0.05 between basal and MET. IF images were obtained at 60X magnification.</p>", "links"=>[], "tags"=>["induced", "nrf2", "translocation", "antioxidant"], "article_id"=>242268, "categories"=>["Physiology", "Biochemistry", "Genetics"], "users"=>["Sellamuthu S. Gounder", "Sankaranarayanan Kannan", "Dinesh Devadoss", "Corey J. Miller", "Kevin S. Whitehead", "Shannon J. Odelberg", "Matthew A. Firpo", "Robert Paine III", "John R. Hoidal", "E. Dale Abel", "Namakkal S. Rajasekaran"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045697.g007", "stats"=>{"downloads"=>3, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Exercise_training_induced_Nrf2_nuclear_translocation_and_increased_antioxidant_levels_/242268", "title"=>"Exercise training induced Nrf2 nuclear translocation and increased antioxidant levels.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 22:53:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/571117"], "description"=>"<p>Immunoblots showing antioxidant enzymes in hearts of young (2 months) and old (>23 months) mice. About 30 µg of cytosolic proteins from ventricle tissues were resolved on PAGE and probed for respective antibodies. Significant (p<0.05) differences were observed between WT and Nrf2-/- mice at older age (n = 4–6/group).</p>", "links"=>[], "tags"=>["antioxidants"], "article_id"=>241606, "categories"=>["Physiology", "Biochemistry", "Genetics"], "users"=>["Sellamuthu S. Gounder", "Sankaranarayanan Kannan", "Dinesh Devadoss", "Corey J. Miller", "Kevin S. Whitehead", "Shannon J. Odelberg", "Matthew A. Firpo", "Robert Paine III", "John R. Hoidal", "E. Dale Abel", "Namakkal S. Rajasekaran"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045697.g002", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Myocardial_antioxidants_in_young_and_old_mice_/241606", "title"=>"Myocardial antioxidants in young and old mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 22:50:23"}

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Relative Metric

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