title: Induction of antioxidant gene expression in a mouse model of ischemic cardiomyopathy is dependent on reactive oxygen species.
abstract: Ischemia and reperfusion (I/R) are characterized by oxidative stress as well as changes in the antioxidant enzymes of the heart. However, little is known about the transcriptional regulation of myocardial antioxidant enzymes in repetitive I/R and hibernating myocardium. In a mouse model of ischemic cardiomyopathy induced by repetitive I/R, we postulated that induction of antioxidant gene expression was dependent on reactive oxygen species (ROS). Repetitive closed-chest I/R (15 min) was performed daily in C57/BL6 mice and in mice overexpressing extracellular superoxide dismutase (EC-SOD). Antioxidant enzyme expression was measured at 3, 5, 7, and 28 days of repetitive I/R as well as 15 and 30 days after discontinuation of I/R. In order to determine whether ROS directly modulates antioxidant gene expression, transcript levels were measured in cardiomyocytes exposed to hydrogen peroxide. Repetitive I/R caused an early and sustained increase in glutathione peroxidase (GPX) transcript levels, while heme oxygenase-1 (HO-1) expression increased only after 7 days of repetitive I/R. Overexpression of EC-SOD prevented the upregulation of GPX and HO-1 transcript levels by repetitive I/R, suggesting that both genes are regulated by ROS. However, while HO-1 transcript levels increased in cardiomyocytes exposed to hydrogen peroxide, oxidative stress failed to induce the expression of GPX implying that ROS regulates GPX transcript levels only indirectly in repetitive I/R. In conclusion, repetitive I/R was associated with an early upregulation of GPX expression as well as a delayed increase of HO-1 transcript levels in the heart. The induction of both antioxidant genes was dependent on ROS, suggesting that alterations in redox balance mediate not only tissue injury but also components of "programmed cell survival" in hibernating myocardium.
authors.affiliation: Cardiology, The University of Texas Houston Medical School, USA.
authors.forename: Saumya
authors.initials: S
authors.lastname: Sharma
authors.forename: Oliver
authors.initials: O
authors.lastname: Dewald
authors.forename: Julia
authors.initials: J
authors.lastname: Adrogue
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Salazar
authors.forename: Peter
authors.initials: P
authors.lastname: Razeghi
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.forename: Russell P
authors.initials: RP
authors.lastname: Bowler
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
authors.forename: Heinrich
authors.initials: H
authors.lastname: Taegtmeyer
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002374:Catalase / Q000235:genetics; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D005979:Glutathione Peroxidase / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics; D050050:Protein Carbonylation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D002374:Catalase; D005979:Glutathione Peroxidase; D051547:Heme Oxygenase-1; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase