Effect of tumor necrosis factor-alpha on endothelial and inducible nitric oxide synthase messenger ribonucleic acid expression and nitric oxide synthesis in ischemic and nonischemic isolated rat heart

Yosef Paz, Inna Frolkis, Dimitri Pevni, Itzhak Shapira, Yael Yuhas, Adrian Iaina, Yoram Wollman, Tamara Chernichovski, Nahum Nesher, Chaim Locker, Rephael Mohr, Gideon Uretzky

Research output: Contribution to journalArticlepeer-review

Abstract

OBJECTIVES: The present study aimed to investigate the influence of endogenous tumor necrosis factor-alpha (TNF-α) that was synthesized during ischemia and exogenous TNF-α on endothelial and inducible nitric oxide synthase (eNOS and iNOS) messenger ribonucleic acid (mRNA) expression and nitric oxide (NO) production in the isolated rat heart. BACKGROUND: Tumor necrosis factor-α is recognized as being a proinflammatory cytokine with a significant cardiodepressant effect. One of the proposed mechanisms for TNF-α-induced cardiac contractile dysfunction is increased NO production via iNOS mRNA upregulation, but the role of NO in TNF-α-induced myocardial dysfunction is highly controversial. METHODS: Isolated rat hearts studied by a modified Langendorff model were randomly divided into subgroups to investigate the effect of 1-h global cardioplegic ischemia or the effect of 1-h perfusion with exogenous TNF-α on the expression of eNOS mRNA and iNOS mRNA and on NO production. RESULTS: After 1 h of ischemia, there were significant increases in TNF levels in the effluent (from hearts), and eNOS mRNA expression had declined (from 0.91 ± 0.0g to 0.68 ± 0.19, p < 0.001); but there were no changes in iNOS mRNA expression, and NO was below detectable levels. Perfusion of isolated hearts with TNF-a had a cardiodepressant effect and decreased eNOS mRNA expression to 0.67 ± 0. 04 (p < 0.002). Inducible nitric oxide synthase mRNA was unchanged, and NO was below detectable levels. CONCLUSIONS: We believe this is the first study to directly show that TNF-α does not increase NO synthesis and release but does downregulate eNOS mRNA in the ischemic and nonischemic isolated rat heart.

Original languageEnglish
Pages (from-to)1299-1305
Number of pages7
JournalJournal of the American College of Cardiology
Volume42
Issue number7
DOIs
StatePublished - 1 Oct 2003

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