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

• Published in: Circulation (New York, N.Y.) N.Y.), 2000-10, Vol.102 (14), p.1690-1696
• Main Authors: XIA LI, MOODY, Melanie R, ENGEL, David, WALKER, Stacey, CLUBB, Fred J, SIVASUBRAMANIAN, Natarajan, MANN, Douglas L, REID, Michael B
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biological and medical sciences; Cardiology. Vascular system; Diaphragm - cytology; Diaphragm - metabolism; Diaphragm - physiology; Heart; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle Contraction; Organ Size; Oxidants - metabolism; Oxidative Stress - physiology; Receptors, Tumor Necrosis Factor - metabolism; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - physiology
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.102.14.1690

We have developed a transgenic mouse with cardiac-restricted overexpression of tumor necrosis factor-alpha (TNF-alpha). These mice develop a heart failure phenotype characterized by left ventricular dysfunction and remodeling, pulmonary edema, and elevated levels of TNF-alpha in the peripheral circulation from cardiac spillover. Given that TNF-alpha 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. 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/cm(2); P: