Genetic redox preconditioning differentially modulates AP-1 and NF kappa B responses following cardiac ischemia/reperfusion injury and protects against necrosis and apoptosis.
Reactive oxygen species have been established as key mediators of cardiac injury following ischemia/reperfusion (I/R). We hypothesized that superoxide formation at different subcellular locations following cardiac I/R injury may differentially regulate cellular responses that determine pathophysiologic outcomes. Recombinant adenoviruses expressing Cu/ZnSOD or MnSOD were utilized to modulate superoxide levels in the cytoplasmic or mitochondrial compartments, respectively, prior to coronary artery I/R injury in the rat heart. Ectopic expression of both MnSOD and Cu/ZnSOD afforded protection from I/R injury, as evidenced by a significant reduction in serum creatine kinase levels, infarct size, malondialdehyde levels, and apoptotic cell death in comparison to controls. MnSOD and Cu/ZnSOD expression also significantly altered the kinetics of NF kappa B and AP-1 activation following I/R injury, characterized by a delayed induction of NF kappa B and abrogated AP-1 response. Western blot analysis of Bcl-2, Bcl-xL, Bad, Caspase 3, PDK1, and phospho-Akt also revealed SOD-mediated changes in gene expression consistent with protection and decreased apoptosis. These findings support the notion that both mitochondrial and cytoplasmic-derived SOD induce changes in AP-1 and NF kappa B activity, creating an antiapoptotic microenvironment within cardiomyocytes that affords protection following I/R injury.
Yang
Jusan
J
Department of Anatomy & Cell Biology, The Center for Gene Therapy of Cystic Fibrosis and Other Genetic Disorders, University of Iowa College of Medicine, Iowa City, Iowa 52242 USA.
Marden
Jennifer J
JJ
Fan
Chenguang
C
Sanlioglu
Salih
S
Weiss
Robert M
RM
Ritchie
Teresa C
TC
Davisson
Robin L
RL
Engelhardt
John F
JF
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D003402:Creatine Kinase / Q000097:blood; D019254:Genes, bcl-2 / Q000235:genetics; D015316:Genetic Therapy; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016328:NF-kappa B / Q000378:metabolism*; D009336:Necrosis; D009363:Neoplasm Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
C494821:Bad protein, rat; C494813:Bcl2l1 protein, rat; D002352:Carrier Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D008315:Malondialdehyde; D013482:Superoxide Dismutase; D003402:Creatine Kinase; D020169:Caspases