From the Cardiology Section of the Department of Medicine, Veterans
Administration Medical Center, Baylor College of Medicine, Houston, Tex.
Background—Previous studies in
isolated cardiac myocytes have shown that tumor necrosis factor
(TNF)-
Methods and Results—To determine whether TNF-
Conclusions—Taken together, the above observations demonstrate
that TNF-
© 1998 American Heart Association, Inc.
Basic Science Reports
Tumor Necrosis Factor-
Confers Resistance to Hypoxic Injury in the Adult Mammalian Cardiac Myocyte
provokes increased expression of 27- and 70-kD stress
proteins as well as manganese superoxide dismutase, suggesting that
TNF- might play a role in mediating stress responses in the
heart. stimulation
would protect isolated cardiac myocytes against environmental stress,
myocyte cultures were pretreated with TNF- for 12 hours and then
subjected to continuous hypoxic injury (O2 content, 3 to 5
ppm) for 12 hours, followed by reoxygenation. Cell
injury was assessed in terms of lactic dehydrogenase (LDH) release,
45Ca2+ uptake, and MTT metabolism.
Pretreatment with TNF- concentrations 
50 U/mL significantly
attenuated LDH release by hypoxic cells compared with diluent-treated
hypoxic cells. Similar findings were observed with respect to
45Ca2+ uptake and MTT metabolism in
TNF-–pretreated cells that were subjected to prolonged
hypoxia. To determine the mechanism for the TNF-–induced
protective effect, the cells were pretreated with heat shock protein
(HSP) 72 antisense oligonucleotides. These studies
showed that the protective effect of TNF- was not inhibited by
antisense oligonucleotides, despite use of a
concentration of antisense that was sufficient to attenuate the
TNF-–induced increase in HSP 72 expression. Subsequent studies
using mutated TNF ligands showed that activation of both types 1 and 2
TNF receptors was sufficient to confer a protective response in
isolated cardiac myocytes through an as yet unknown pathway(s). pretreatment confers resistance to hypoxic stress in the
adult cardiac myocyte through a novel mechanism that appears to be
different from but not necessarily exclusive of the protective response
conferred by HSP 72 expression.
Key Words: myocytes • hypoxia • proteins • genes
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