Cardiac-specific overexpression of tumor necrosis factor-α causes oxidative stress and contractile dysfunction in mouse diaphragm

Xia Li, Melanie R. Moody, David Engel, Stacey Walker, Fred J. Clubb, Natarajan Sivasubramanian, Douglas L. Mann, Michael B. Reid

Research output: Contribution to journalArticle

166 Scopus citations

Abstract

Background - We have developed a transgenic mouse with cardiac-restricted overexpression of tumor necrosis factor-α (TNF-α). These mice develop a heart failure phenotype characterized by left ventricular dysfunction and remodeling, pulmonary edema, and elevated levels of TNF-α in the peripheral circulation from cardiac spillover. Given that, TNF-α causes atrophy and loss of function in respiratory muscle, we asked whether transgenic mice developed diaphragm dysfunction and Whether contractile losses were caused by oxidative stress or tissue remodeling. Methods and Results - Muscles excised from transgenic mice and littermate controls were studied in vitro with direct electrical stimulation. Cytosolic oxidant levels were measured with 2',7'-dichlorofluorescin diacetate; emissions of the oxidized product were detected by fluorescence microscopy. Force generation by the diaphragm of transgenic animals was 47% less than control (13.2±0.8 [±SEM] versus 25.1±0.6 N/cm2; P<0.001); this weakness was associated with greater intracellular oxidant levels (P<0.025) and was partially reversed by 30-minute incubation with the antioxidant N-acetylcysteine 10 mmol/L (P<0.01). Exogenous TNF-α 500 μmol/L increased oxidant production in diaphragm of wild-type mice and caused weakness that was inhibited by N-acetylcysteine, suggesting that changes observed in the diaphragm of transgenic animals were mediated by TNF-α. There were no differences in body or diaphragm weights between transgenic and control animals, nor was there evidence of muscle injury or apoptosis. Conclusions - Elevated circulating levels of TNF-α provoke contractile dysfunction in the diaphragm through an endocrine mechanism thought to be mediated by oxidative stress.

Original languageEnglish
Pages (from-to)1690-1696
Number of pages7
JournalCirculation
Volume102
Issue number14
DOIs
StatePublished - Oct 3 2000
Externally publishedYes

Keywords

  • Antioxidants
  • Cytokines
  • Free radicals
  • Heart failure
  • Muscles
  • Myocytes

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