Abstract
Incubation with TNF-α (50 ng/ml) for 72 hours markedly reduced viability of endothelial cells. A 6-hour preincubation with S-nitroso-N-acetyl-D,L-penicillamine (SNAP, 3-100 μM) protected cells in a concentration-dependent manner and decreased TNF-α-mediated toxicity by up to 70%. Cytoprotection by SNAP was completely abolished by the adenylyl cyclase inhibitor 2',5'-dideoxyadenosine and mimicked by 8-bromo cyclic AMP or forskolin. SNAP produced significant increases in cyclic GMP and cyclic AMP, both being abrogated in the presence of the NO scavenger 2-phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl-3-oxide (PTIO). Moreover, no endothelial protection by SNAP was detected in the presence of the protein kinase A inhibitor KT5720, whereas the protein kinase G inhibitor KT5823 left cytoprotection virtually unaltered. Our results demonstrate a crucial role for cyclic AMP in mediating NO-induced endothelial protection against TNF-α, possibly through cyclic GMP-dependent inhibition of cyclic AMP breakdown. NO-dependent endothelial protection may ultimately result from cyclic AMP-induced up-regulation of antioxidant proteins or down-regulation of cytotoxic processes.
Original language | English (US) |
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Pages (from-to) | 460-465 |
Number of pages | 6 |
Journal | Biochemical and Biophysical Research Communications |
Volume | 251 |
Issue number | 2 |
DOIs | |
State | Published - Oct 20 1998 |
Bibliographical note
Funding Information:This work was supported by the Deutsche Forschungsgemein-schaft (Schr 298/8-2). We would like to thank Martina Heidler for secretarial assistance.