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(Circulation. 1999;99:1492-1498.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Tissue Expression and Immunolocalization of Tumor Necrosis Factor-
in Postinfarction Dysfunctional Myocardium
From The Centre for Cardiovascular Research, The Toronto Hospital (M.W.I., S.M., R.Q., A.Y., F.D., W.H.W., Z.S., P.L.), Amgen Institute, Ontario Cancer Institute, and Departments of Medical Biophysics and Immunology (J.M.P.), University of Toronto, Canada, and VA Medical Center, Baylor College of Medicine, Houston, Tex (D.L.M.).
Correspondence to Peter Liu, MD, 12 EC-324, The Toronto Hospital, General Division, Toronto, Ontario M5G 2C4, Canada. E-mail peter.liu{at}utoronto.ca
Background—Tumor necrosis
factor-
(TNF-) is markedly elevated in advanced heart failure. It
is not known whether tissue TNF- is elevated in the common setting
of myocardial infarction leading to heart failure and what the source
of TNF- is. To determine this, we studied the expression and protein
localization of TNF- and its 2 main receptors (TNF-R1/R2) in a rat
model of large infarction.
Methods and Results—Male rats were randomized to proximal left
anterior descending ligation. The animals were killed on days 1, 3, 10,
and 35 after ligation to examine gene expression and protein
production of TNF- and TNF-R1/R2 from the infarct,
peri-infarct, and contralateral zones of infarcted heart. There was
increased TNF- mRNA production throughout the
myocardium at day 1, and detectable expression persisted to
day 35 after myocardial infarction. The expression of this
cytokine is not confined strictly to the infarct or
peri-infarct zones but is expressed by cardiac myocytes within the
myocardium in the contralateral normal zone. Changes in
gene expression are mirrored initially by augmented protein
production within the myocytes. Levels of TNF- protein in
the infarct and peri-infarct zones rose early to 8- to 10-fold above
normal levels and rose to 4- to 5-fold in the contralateral zone.
Finally, expression of the TNF-R1 mRNA transcripts was upregulated at
days 3 and 10 after ligation in the infarct and peri-infarct zones,
suggesting that the signal transduction pathways necessary for TNF-
in the heart remain intact as TNF- biosynthesis increases.
Conclusions—TNF- is present early in a model of large
myocardial infarction and is sustained into the later stage within the
myocardium. Expression of this cytokine is not only
confined strictly to the infarct or peri-infarct zone but is expressed
by cardiac myocytes within the myocardium contralateral to
the infarct. Therefore TNF- production forms a part of an
important intrinsic myocardial stress response system to injury.
Key Words: tissue • myocardium • infarction • heart failure • remodeling • cytokines • tumor necrosis factor
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