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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
Journal article   Open access   Peer reviewed

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

Yan Li, Adam R Wende, Orathai Nunthakungwan, Yujia Huang, Eric Hu, Huifeng Jin, Sihem Boudina, E Dale Abel and Thunder Jalili
The FEBS journal, Vol.279(4), pp.599-611
02/2012
DOI: 10.1111/j.1742-4658.2011.08450.x
PMCID: PMC3267000
PMID: 22221582
url
https://www.ncbi.nlm.nih.gov/pmc/articles/3267000View
Open Access

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

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