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Nitric oxide prevents 6-hydroxydopamine-induced apoptosis in PC12 cells through cGMP-dependent PI3 kinase/Akt activation.
- Source :
-
FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2003 Jun; Vol. 17 (9), pp. 1036-47. - Publication Year :
- 2003
-
Abstract
- Nitric oxide (NO) functions not only as an important signaling molecule in the brain by producing cGMP, but also regulates neuronal cell apoptosis. The mechanism by which NO regulates apoptosis is unclear. In this study, we demonstrated that NO, produced either from the NO donor S-nitroso-N-acetyl-d,l-penicillamine (SNAP) or by transfection of neuronal NO synthase, suppressed 6-hydroxydopamine (6-OHDA)-induced apoptosis in PC12 cells by inhibiting mitochondrial cytochrome c release, caspase-3 and -9 activation, and DNA fragmentation. This protection was significantly reversed by the soluble guanylyl cyclase inhibitor 1H-(1,2,4)-oxadiazole[4,3-a]quinoxalon-1-one, indicating that cGMP is a key mediator in NO-mediated anti-apoptosis. Moreover, the membrane-permeable cGMP analog 8-Br-cGMP inhibited 6-OHDA-induced apoptosis. These anti-apoptotic effects of SNAP and 8-Br-cGMP were suppressed by cGMP-dependent protein kinase G (PKG) inhibitor KT5823, indicating that PKG is a downstream signal mediator in the suppression of apoptosis by NO and cGMP. Both SNAP and 8-Br-cGMP induced endogenous Akt activation and Bad phosphorylation, resulting in the inhibition of Bad translocation to mitochondria; these effects were inhibited by KT5823 and the phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 and Wortmannin. Our data suggest that the NO/cGMP pathway suppresses 6-OHDA-induced PC12 cell apoptosis by suppressing the mitochondrial apoptosis signal via PKG/PI3K/Akt-dependent Bad phosphorylation.
- Subjects :
- Anilides metabolism
Animals
Caspase 3
Caspases metabolism
Cell Differentiation
Cyclic GMP-Dependent Protein Kinases metabolism
Cytochrome c Group metabolism
Cytoprotection
Enzyme Activation
Neurons cytology
Neurons drug effects
Nitric Oxide Donors pharmacology
Nitric Oxide Synthase genetics
Nitric Oxide Synthase Type I
Oligopeptides metabolism
PC12 Cells
Penicillamine pharmacology
Proto-Oncogene Proteins c-akt
Rats
Transfection
Apoptosis
Cyclic GMP physiology
Neurons enzymology
Nitric Oxide physiology
Oxidopamine antagonists & inhibitors
Penicillamine analogs & derivatives
Phosphatidylinositol 3-Kinases metabolism
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1530-6860
- Volume :
- 17
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publication Type :
- Academic Journal
- Accession number :
- 12773486
- Full Text :
- https://doi.org/10.1096/fj.02-0738com