title: Abrogation of Nrf2 impairs antioxidant signaling and promotes atrial hypertrophy in response to high-intensity exercise stress.
abstract: BACKGROUND
  Anomalies in myocardial structure involving myocyte growth, hypertrophy, differentiation, apoptosis, necrosis etc. affects its function and render cardiac tissue more vulnerable to the development of heart failure. Although oxidative stress has a well-established role in cardiac remodeling and dysfunction, the mechanisms linking redox state to atrial cardiomyocyte hypertrophic changes are poorly understood. Here, we investigated the role of nuclear erythroid-2 like factor-2 (Nrf2), a central transcriptional mediator, in redox signaling under high intensity exercise stress (HIES) in atria.
  
  
  METHODS
  Age and sex-matched wild-type (WT) and Nrf2(-/-) mice at >20 months of age were subjected to HIES for 6 weeks. Gene markers of hypertrophy and antioxidant enzymes were determined in the atria of WT and Nrf2(-/-) mice by real-time qPCR analyses. Detection and quantification of antioxidants, 4-hydroxy-nonenal (4-HNE), poly-ubiquitination and autophagy proteins in WT and Nrf2(-/-) mice were performed by immunofluorescence analysis. The level of oxidative stress was measured by microscopical examination of di-hydro-ethidium (DHE) fluorescence.
  
  
  RESULTS
  Under the sedentary state, Nrf2 abrogation resulted in a moderate down regulation of some of the atrial antioxidant gene expression (Gsr, Gclc, Gstα and Gstµ) despite having a normal redox state. In response to HIES, enlarged atrial myocytes along with significantly increased gene expression of cardiomyocyte hypertrophy markers (Anf, Bnf and β-Mhc) were observed in Nrf2(-/-) when compared to WT mice. Further, the transcript levels of Gclc, Gsr and Gstµ and protein levels of NQO1, catalase, GPX1 were profoundly downregulated along with GSH depletion and increased oxidative stress in Nrf2(-/-) mice when compared to its WT counterparts after HIES. Impaired antioxidant state and profound oxidative stress were associated with enhanced atrial expression of LC3 and ATG7 along with increased ubiquitination of ATG7 in Nrf2(-/-) mice subjected to HIES.
  
  
  CONCLUSIONS
  Loss of Nrf2 describes an altered biochemical phenotype associated with dysregulation in genes related to redox state, ubiquitination and autophagy in HIES that result in atrial hypertrophy. Therefore, our findings direct that preserving Nrf2-related antioxidant function would be one of the effective strategies to safeguard atrial health.
authors.affiliation: Cardiac Aging & Redox Signaling Laboratory, Division of Molecular & Cellular Pathology, Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, 35294-2180, USA.
authors.forename: Radhakrishnan Rajesh
authors.initials: RR
authors.lastname: Kumar
authors.affiliation: Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX, 79430, USA.
authors.forename: Madhusudhanan
authors.initials: M
authors.lastname: Narasimhan
authors.affiliation: Cardiac Aging & Redox Signaling Laboratory, Division of Molecular & Cellular Pathology, Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, 35294-2180, USA.
authors.forename: Gobinath
authors.initials: G
authors.lastname: Shanmugam
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, The University of Utah School of Medicine, Salt Lake City, UT, 84132, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hong
authors.affiliation: Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.
authors.forename: Asokan
authors.initials: A
authors.lastname: Devarajan
authors.affiliation: Department of Bio-Engineering, Comprehensive Cardiovascular Center, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Sethu
authors.initials: S
authors.lastname: Palaniappan
authors.affiliation: Center for Free Radical Biology, The University of Alabama at Birmingham, Birmingham, AL, 35294-2180, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Comprehensive Cardiovascular Center, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Ganesh V
authors.initials: GV
authors.lastname: Halade
authors.affiliation: Center for Free Radical Biology, The University of Alabama at Birmingham, Birmingham, AL, 35294-2180, USA.
authors.forename: Victor M
authors.initials: VM
authors.lastname: Darley-Usmar
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, The University of Utah School of Medicine, Salt Lake City, UT, 84132, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Hoidal
authors.affiliation: Cardiac Aging & Redox Signaling Laboratory, Division of Molecular & Cellular Pathology, Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, 35294-2180, USA. rajnsr@uab.edu.|Division of Cardiovascular Medicine, Department of Medicine, The University of Utah School of Medicine, Salt Lake City, UT, 84132, USA. rajnsr@uab.edu.|Center for Free Radical Biology, The University of Alabama at Birmingham, Birmingham, AL, 35294-2180, USA. rajnsr@uab.edu.|Department of Exercise Physiology, College of Health, The University of Utah School of Medicine, Salt Lake City, UT, 84132, USA. rajnsr@uab.edu.
authors.forename: Namakkal S
authors.initials: NS
authors.lastname: Rajasekaran
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001343:Autophagy; D015536:Down-Regulation / Q000235:genetics; D005455:Fluorescent Antibody Technique; D017353:Gene Deletion; D005978:Glutathione / Q000378:metabolism; D006325:Heart Atria / Q000378:metabolism* / Q000473:pathology*; D006984:Hypertrophy; D015227:Lipid Peroxidation; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000378:metabolism*; D018384:Oxidative Stress; D010805:Physical Conditioning, Animal; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological; D014158:Transcription, Genetic; D057149:Ubiquitinated Proteins / Q000378:metabolism
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D057149:Ubiquitinated Proteins; D005978:Glutathione
keywords: Antioxidants; Atrial hypertrophy; Autophagy; Nrf2 knockout; Oxidative stress