Cytosolic, but not mitochondrial, oxidative stress is a likely contributor to
cardiac hypertrophy resulting from cardiac specific GLUT4 deletion in mice.
Authors Li Y, Wende AR, Nunthakungwan O, Huang Y, Hu E, Jin H, Boudina S, Abel ED,
Jalili T
Submitted By Submitted Externally on 3/4/2015
Status Published
Journal The FEBS journal
Year 2012
Date Published 2/1/2012
Volume : Pages 279 : 599 - 611
PubMed Reference 22221582
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 3ß 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.

Investigators with authorship
E. Dale AbelUniversity of Iowa
Adam WendeUniversity of Alabama at Birmingham