Background - Tumor necrosis factor-α (TNF-α) is markedly elevated in advanced heart failure. It is not known whether tissue TNF-α is elevated in the common setting of myocardial infarction leading to heart failure and what the source of TNF-α is. To determine this, we studied the expression and protein localization of TNF-α 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-α and TNF-R1/R2 from the infarct, peri-infarct, and contralateral zones of infarcted heart. There was increased TNF-α 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-α 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-α in the heart remain intact as TNF-α biosynthesis increases. Conclusions - TNF-α 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- α production forms a part of an important intrinsic myocardial stress response system to injury.
- Heart failure
- Tumor necrosis factor