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Cytosolic, but not mitochondrial, oxidative stress is a likely contributor to cardiac hypertrophy resulting from cardiac specific GLUT4 deletion in mice
Author(s) -
Li Yan,
Wende Adam R.,
Nunthakungwan Orathai,
Huang Yujia,
Hu Eric,
Jin Huifeng,
Boudina Sihem,
Abel E. Dale,
Jalili Thunder
Publication year - 2012
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2011.08450.x
Subject(s) - oxidative stress , glut4 , medicine , endocrinology , glutathione , reactive oxygen species , muscle hypertrophy , glutathione reductase , mitochondrion , chemistry , oxidative phosphorylation , glutathione disulfide , nadph oxidase , biology , glutathione peroxidase , biochemistry , glucose uptake , insulin , catalase , enzyme
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 m m , 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.