(Circulation. 2000;102:1690.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Cardiac-Specific Overexpression of Tumor Necrosis Factor-
Causes Oxidative Stress and Contractile Dysfunction in Mouse Diaphragm
From Baylor College of Medicine and Texas Heart Institute (F.J.C.), Houston, Tex.
Correspondence to Michael B. Reid, PhD, Pulmonary Medicine, Suite 520B, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. E-mail reid{at}bcm.tmc.edu
Background—We have developed a
transgenic mouse with cardiac-restricted overexpression of tumor
necrosis factor-
(TNF-). These mice develop a heart failure
phenotype characterized by left ventricular
dysfunction and remodeling, pulmonary edema, and elevated
levels of TNF- in the peripheral circulation from
cardiac spillover. Given that TNF- 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- 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-. 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- provoke
contractile dysfunction in the diaphragm through an endocrine mechanism
thought to be mediated by oxidative stress.
Key Words: heart failure • muscles • myocytes • free radicals • antioxidants • cytokines
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