Nitric oxide provokes tumor necrosis factor-α expression in adult feline myocardium through a cGMP-dependent pathway

Dinesh Kalra, Georg Baumgarten, Ziad Dibbs, Yukihiro Seta, Natarajan Sivasubramanian, Douglas L. Mann

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

Abstract

Background - The mechanism(s) responsible for the persistent coexpression of tumor necrosis factor-α (TNF-α) and nitric oxide (NO) in the failing heart is unknown. Methods and Results - To determine whether NO was sufficient to provoke TNF-α biosynthesis, we examined the effects of an NO donor, S-nitroso-N-acetyl penicillamine (SNAP), in buffer-perfused Langendorff hearts. SNAP (1 μmol/L) treatment resulted in a time- and dose-dependent increase in myocardial TNF-α mRNA and protein biosynthesis in adult cat hearts. The effects of SNAP were completely abrogated by a NO quenching agent, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (C-PTIO), and mimicked by sodium nitroprusside. Electrophoretic mobility shift assays demonstrated that SNAP treatment led to the rapid induction of nuclear factor kappa-beta (NF-κB) but not AP-1. The importance of the cGMP pathway in terms of mediating NO-induced TNF-α biosynthesis was shown by studies that demonstrated that 8-bromo-cGMP mimicked the effects of SNAP and that the effects of SNAP could be completely abrogated using a cGMP antagonist, 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), or protein kinase G antagonist (Rp-8-Br-cGMPS). SNAP and 8-Br-cGMP were both sufficient to lead to the site-specific phosphorylation (serine 32) and degradation of IκBα in isolated cardiac myocytes. Finally, protein kinase G was sufficient to directly phosphorylate IκBα on serine 32, a critical step in the activation of NF-κB. Conclusions - These studies show that NO provokes TNF-α biosynthesis through a cGMP-dependent pathway, which suggests that the coincident expression of TNF-α and NO may foster self-sustaining positive autocrine/paracrine feedback inflammatory circuits within the failing heart.

Original languageEnglish
Pages (from-to)1302-1307
Number of pages6
JournalCirculation
Volume102
Issue number11
DOIs
StatePublished - Sep 12 2000

Keywords

  • Cyclic GMP
  • Heart failure, congestive
  • NF-κB
  • Nitric oxide
  • Tumor necrosis factor

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