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Angiotension II induced insulin resistance and mitochondrial disruption are diminished in p47phox deficient mice
Author(s) -
Stump Craig,
Chen Guanjie,
Booth Allyson,
DiamondStanic Maggie,
Henriksen Erik
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1095.1
Subject(s) - medicine , endocrinology , insulin resistance , nadph oxidase , skeletal muscle , angiotensin ii , mitochondrion , insulin , oxidative stress , lipid peroxidation , biology , reactive oxygen species , chemistry , biochemistry , blood pressure
We hypothesized that the renin‐angiotensin system (RAS) impairs insulin action in skeletal muscle via NADPH oxidase‐dependent mitochondrial dysfunction and reactive oxygen species production. Pathogen free B6(Cg)‐ Ncf1 m1J /J mice (Jackson Laboratory), which harbor an inactivating mutation for the p47phox subunit of NADPH oxidase, and C57/BL6J (C57) control mice were treated with either vehicle (Sham) or angiotensin II (Ang II) by osmotic pump (1.44 mg/kg/d) for two weeks. Soleus muscle ( ex vivo ) response to insulin for glucose uptake was significantly decreased in Ang II‐infused C57 mice (34%; p<0.05), but not in B6(Cg)‐ Ncf1 m1J /J mice, suggesting that NADPH oxidase activation is required for Ang II‐induced muscle insulin resistance. In addition, 4‐HNE immunostaining, a marker of lipid peroxidation, was significantly higher (35%) in hindlimb muscles from Ang II‐infused C57 than in B6(Cg)‐ Ncf1 m1J /J mice. Electron microscopy (EM) also showed that Ang II infusion markedly disrupted mitochondrial membrane and cristae integrity in the C57 mouse skeletal muscle. However, Ang II induced mitochondrial changes were abrogated in p47phox deficient mouse muscle. In summary, the adverse effects of Ang II on muscle mitochondria and insulin sensitivity were diminished in mice with a p47phox subunit inactivating mutation. Supported by an Endocrine Society Research Award.