Nitric Oxide Provokes Tumor Necrosis Factor-α Expression in Adult Feline Myocardium Through a cGMP-Dependent Pathway

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 S...