title: Protection from oxidative and electrophilic stress in the Gsta4-null mouse heart.
abstract: 4-Hydroxynonenal (4-HNE) mediates many pathological effects of oxidative and electrophilic stress and signals to activate cytoprotective gene expression regulated by NF-E2-related factor 2 (Nrf2). By exhibiting very high levels of 4-HNE-conjugating activity, the murine glutathione transferase alpha 4 (GSTA4-4) helps regulate cellular 4-HNE levels. To examine the role of 4-HNE in vivo, we disrupted the murine Gsta4 gene. Gsta4-null mice exhibited no cardiac phenotype under normal conditions and no difference in cardiac 4-HNE level as compared to wild-type mice. We hypothesized that the Nrf2 pathway might contribute an important compensatory mechanism to remove excess cardiac 4-HNE in Gsta4-null mice. Cardiac nuclear extracts from Gsta4-null mice exhibited significantly higher Nrf2 binding to antioxidant response elements. We also observed responses in critical Nrf2 target gene products: elevated Sod2, Cat, and Akr1b7 mRNA levels and significant increases in both cardiac antioxidant and anti-electrophile enzyme activities. Gsta4-null mice were less sensitive and maintained normal cardiac function following chronic doxorubicin treatment, known to increase cardiac 4-HNE levels. Hence, in the absence of GSTA4-4 to modulate both physiological and pathological 4-HNE levels, the adaptive Nrf2 pathway may be primed to contribute to a preconditioned cardiac phenotype in the Gsta4-null mouse.
authors.affiliation: Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Beneš
authors.forename: Mai K
authors.initials: MK
authors.lastname: Vuong
authors.forename: Marjan
authors.initials: M
authors.lastname: Boerma
authors.forename: Kevin E
authors.initials: KE
authors.lastname: McElhanon
authors.forename: Eric R
authors.initials: ER
authors.lastname: Siegel
authors.forename: Sharda P
authors.initials: SP
authors.lastname: Singh
mesh_terms: D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D004317:Doxorubicin / Q000633:toxicity; D005982:Glutathione Transferase / Q000172:deficiency* / Q000235:genetics; D006321:Heart / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D050984:NF-E2 Transcription Factor, p45 Subunit / Q000235:genetics / Q000502:physiology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011485:Protein Binding / Q000235:genetics
chemical_list: D000447:Aldehydes; D050984:NF-E2 Transcription Factor, p45 Subunit; C494693:Nfe2 protein, mouse; D004317:Doxorubicin; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase; C027576:4-hydroxy-2-nonenal