Cytosolic, but not mitochondrial, oxidative stress is a likely contributor to cardiac hypertrophy resulting from cardiac specific GLUT4 deletion in mice

Academic Article

Abstract

  • We hypothesized that oxidative stress may contribute to the development of hypertrophy observed in mice with cardiac specific ablation of the insulin sensitive glucose transporter 4 gene (GLUT4, G4H -/- ). Measurements of oxidized glutathione (GSSG) in isolated mitochondria and whole heart homogenates were increased resulting in a lower ratio of reduced glutathione (GSH) to GSSG. Membrane translocation of the p67 phox subunit of cardiac NADPH oxidase 2 (NOX2) was markedly increased in G4H -/- mice, suggesting elevated activity. To determine if oxidative stress was contributing to cardiac hypertrophy, 4-week-old control (Con) and G4H -/- mice were treated with either tempol (T, 1 mm, drinking water), a whole cell antioxidant, or Mn(III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP, 10 mg·kg -1 , intraperitoneally), a mitochondrial targeted antioxidant, for 28 days. Tempol attenuated cardiac hypertrophy in G4H -/- mice (heart: tibia, Con 6.82 ± 0.35, G4H -/- 8.83 ± 0.34, Con + T 6.82 ± 0.46, G4H -/- + T 7.57 ± 0.3), without changing GSH: GSSG, glutathione peroxidase 4 or membrane translocation of the p67 phox . Tempol did not modify phosphorylation of glycogen synthase kinase 3β or thioredoxin-2. In contrast, MnTBAP lowered mitochondrial GSSG and improved GSH: GSSG, but did not prevent hypertrophy, indicating that mitochondrial oxidative stress may not be critical for hypertrophy in this model. The ability of tempol to attenuate cardiac hypertrophy suggests that a cytosolic source of reactive oxygen species, probably NOX2, may contribute to the hypertrophic phenotype in G4H -/- mice. © 2011 The Authors Journal compilation © 2011 FEBS.
  • Authors

    Digital Object Identifier (doi)

    Pubmed Id

  • 23873945
  • Author List

  • Li Y; Wende AR; Nunthakungwan O; Huang Y; Hu E; Jin H; Boudina S; Abel ED; Jalili T
  • Start Page

  • 599
  • End Page

  • 611
  • Volume

  • 279
  • Issue

  • 4