Cyclic AMP mediates endothelial protection by nitric oxide

Biochem Biophys Res Commun. 1998 Oct 20;251(2):460-5. doi: 10.1006/bbrc.1998.9486.

Abstract

Incubation with TNF-alpha (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 microM) protected cells in a concentration-dependent manner and decreased TNF-alpha-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-alpha, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Bromo Cyclic Adenosine Monophosphate / pharmacology
  • Adenylyl Cyclase Inhibitors
  • Alkaloids / pharmacology
  • Animals
  • Carbazoles*
  • Cattle
  • Cell Line
  • Cell Survival / drug effects
  • Cell Survival / physiology*
  • Colforsin / pharmacology
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic GMP / metabolism
  • Cyclic N-Oxides / pharmacology
  • Dideoxyadenosine / pharmacology
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / physiology*
  • Enzyme Inhibitors / pharmacology
  • Free Radical Scavengers / pharmacology
  • Imidazoles / pharmacology
  • Indoles / pharmacology
  • Kinetics
  • Nitric Oxide / pharmacology
  • Nitric Oxide / physiology*
  • Nitric Oxide Donors / pharmacology
  • Oxadiazoles / pharmacology
  • Penicillamine / analogs & derivatives*
  • Penicillamine / pharmacology
  • Pulmonary Artery
  • Pyrroles / pharmacology
  • Quinoxalines / pharmacology
  • S-Nitroso-N-Acetylpenicillamine
  • Tumor Necrosis Factor-alpha / toxicity

Substances

  • 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one
  • Adenylyl Cyclase Inhibitors
  • Alkaloids
  • Carbazoles
  • Cyclic N-Oxides
  • Enzyme Inhibitors
  • Free Radical Scavengers
  • Imidazoles
  • Indoles
  • Nitric Oxide Donors
  • Oxadiazoles
  • Pyrroles
  • Quinoxalines
  • Tumor Necrosis Factor-alpha
  • KT 5823
  • 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide
  • Colforsin
  • 8-Bromo Cyclic Adenosine Monophosphate
  • Nitric Oxide
  • Dideoxyadenosine
  • KT 5720
  • S-Nitroso-N-Acetylpenicillamine
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Penicillamine
  • Cyclic GMP