title: A biphasic effect of TNF-α in regulation of the Keap1/Nrf2 pathway in cardiomyocytes.
abstract: Antagonizing TNF-α signaling attenuates chronic inflammatory disease, but is associated with adverse effects on the cardiovascular system. Therefore the impact of TNF-α on basal control of redox signaling events needs to be understand in more depth. This is particularly important for the Keap1/Nrf2 pathway in the heart and in the present study we hypothesized that inhibition of a low level of TNF-α signaling attenuates the TNF-α dependent activation of this cytoprotective pathway. HL-1 cardiomyocytes and TNF receptor1/2 (TNFR1/2) double knockout mice (DKO) were used as experimental models. TNF-α (2-5ng/ml, for 2h) evoked significant nuclear translocation of Nrf2 with increased DNA/promoter binding and transactivation of Nrf2 targets. Additionally, this was associated with a 1.5 fold increase in intracellular glutathione (GSH). Higher concentrations of TNF-α (>10-50ng/ml) were markedly suppressive of the Keap1/Nrf2 response and associated with cardiomyocyte death marked by an increase in cleavage of caspase-3 and PARP. In vivo experiments with TNFR1/2-DKO demonstrates that the expression of Nrf2-regulated proteins (NQO1, HO-1, G6PD) were significantly downregulated in hearts of the DKO when compared to WT mice indicating a weakened antioxidant system under basal conditions. Overall, these results indicate that TNF-α exposure has a bimodal effect on the Keap1/Nrf2 system and while an intense inflammatory activation suppresses expression of antioxidant proteins a low level appears to be protective.
authors.affiliation: Cardiac Aging & Redox Signaling Laboratory, Division of Molecular & Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
authors.forename: Gobinath
authors.initials: G
authors.lastname: Shanmugam
authors.affiliation: Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, United States.
authors.forename: Madhusudhanan
authors.initials: M
authors.lastname: Narasimhan
authors.affiliation: Cardiac Aging & Redox Signaling Laboratory, Division of Molecular & Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Sakthivel
authors.affiliation: Cardiac Aging & Redox Signaling Laboratory, Division of Molecular & Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kumar R
authors.affiliation: Division of Cardiovascular, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Davidson
authors.affiliation: Departments of Medicine & Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
authors.forename: Sethu
authors.initials: S
authors.lastname: Palaniappan
authors.affiliation: Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, New Orleans, LA, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Claycomb
authors.affiliation: Pulmonary Medicine, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Hoidal
authors.affiliation: Center for Free Radical Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, United States.
authors.forename: Victor M
authors.initials: VM
authors.lastname: Darley-Usmar
authors.affiliation: Cardiac Aging & Redox Signaling Laboratory, Division of Molecular & Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States; Division of Cardiovascular, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, United States; Center for Free Radical Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, United States. Electronic address: rajnsr@uabmc.edu.
authors.forename: Namakkal Soorappan
authors.initials: NS
authors.lastname: Rajasekaran
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005978:Glutathione / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism*; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D005978:Glutathione
keywords: Antioxidants; Apoptosis; Nrf2 signaling; Oxidative stress; TNF-α