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.
  • Authors

    Published In

    Keywords

  • Animals, Antioxidants, Blotting, Western, Body Weight, Cardiomegaly, Cyclic N-Oxides, Cytosol, Glucose Transporter Type 4, Glutathione, Glutathione Disulfide, Glutathione Peroxidase, Hydrogen Peroxide, Malondialdehyde, Metalloporphyrins, Mice, Mice, Knockout, Mitochondria, Myocardium, Oxidative Stress, Phosphoproteins, Reactive Oxygen Species, Reverse Transcriptase Polymerase Chain Reaction, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Spin Labels, Time Factors
  • 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