Genetic redox preconditioning differentially modulates AP-1 and NF kappa B responses following cardiac ischemia/reperfusion injury and protects against necrosis and apoptosis

YANG J., MARDEN J., FAN C., Sanlioglu S., WEISS R., RITCHIE T., ...Daha Fazla

MOLECULAR THERAPY, cilt.7, sa.3, ss.341-353, 2003 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 7 Sayı: 3
  • Basım Tarihi: 2003
  • Doi Numarası: 10.1016/s1525-0016(02)00061-8
  • Dergi Adı: MOLECULAR THERAPY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.341-353
  • Anahtar Kelimeler: ischemia, reperfusion, apoptosis, heart, infarction, gene therapy, MANGANESE SUPEROXIDE-DISMUTASE, CARDIOMYOCYTE APOPTOSIS, EPITHELIAL-CELLS, CORONARY-ARTERY, REPERFUSION, ACTIVATION, OVEREXPRESSION, HYPOXIA, PHOSPHORYLATION, ISCHEMIA
  • Akdeniz Üniversitesi Adresli: Evet

Özet

Reactive oxygen species have been established as key mediators of cardiac injury following ischemia/reperfusion (I/R). We hypothesized that superoxide formation at differ ent subcellular locations following cardiac l/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 NFkappaB and AP-1 activation following I/R injury, characterized by a delayed induction of NFkappaB 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 NFkappaB activity, creating an antiapoptotic microenvironment within cardiomyocytes that affords protection following I/R injury.