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The Journal of Neuroscience, August 15, 1999, 19(16):6740-6747
Nitric Oxide Protects PC12 Cells from Serum Deprivation-Induced Apoptosis by cGMP-Dependent Inhibition of Caspase Signaling
Young-Myeong Kim1, 2, Hun-Taeg Chung3, Sung-Soo Kim1, Jeong-A Han1, Yeong-Min Yoo1, Ki-Mo Kim1, Gwang-Hoon Lee4, Hye-Young Yun4, Angela Green2, Jianrong Li2, Richard L. Simmons2, and Timothy R. Billiar2 1 Department of Molecular and Cellular Biochemistry, College of Medicine, Kangwon National University, Chunchon, Kangwon-do, Korea, 2 Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, 3 Department of Immunology, Wonkwang University, College of Medicine, Iksan, Chunbug, Korea, and 4 Department of Biochemistry, College of Medicine, Chung-Ang University, Seoul, Korea
Although nitric oxide (NO) induces neuronal cell death under some conditions, it also can prevent apoptosis resulting from growth factor withdrawal. We investigated the molecular mechanism by which NO protects undifferentiated and differentiated PC12 cells from trophic factor deprivation-induced apoptosis. PC12 cells underwent apoptotic death in association with increased caspase-3-like activity, DNA fragmentation, poly(ADP-ribose) polymerase (PARP) cleavage, and cytochrome c release after 24 hr of serum withdrawal. The apoptosis of PC12 cells was inhibited by the addition of NO-generating donor S-nitroso-N-acetylpenicillamine (SNAP) (5-100 µM) and the specific caspase-3-like protease inhibitor Ac-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD-cho) but not the YVADase (or caspase-1-like protease) inhibitor N-acetyl-Tyr-Val-Ala-Asp-aldehyde (Ac-YVAD-cho). SNAP and Ac-DEVD-cho prevented the increase in DEVDase (caspase-3-like protease) activity. The SNAP-mediated suppression of DEVDase activity was only minimally reversed by the incubation of cell lysate with dithiothreitol, indicating that NO did not S-nitrosylate caspase-3-like proteases in PC12 cells. Western blot analysis showed that NO inhibited the proteolytic activation of caspase-3. The cGMP analog 8-bromo-cGMP (8-Br-cGMP) blocked apoptotic cell death, caspase-3 activity and activation, and cytochrome c release. The soluble guanylyl cyclase inhibitor 1-H-oxodiazol-[1,2,4]-[4,3-a] quinoxaline-1-one (CODQ) significantly attenuated NO-mediated, but not 8-Br-cGMP-dependent, inhibition of apoptotic cell death, PARP cleavage, cytochrome c release, and DEVDase activity. Furthermore, the protein kinase G inhibitor KT5823 reversed both SNAP- and 8-Br-cGMP-mediated anti-apoptotic events. All these apoptotic phenomena were also suppressed by NO production through neuronal NO synthase gene transfer into PC12 cells. Furthermore, similar findings were observed in differentiated PC12 cells stimulated to undergo apoptosis by NO donors and NGF deprivation. These findings indicate that NO protects against PC12 cell death by inhibiting the activation of caspase proteases through cGMP production and activation of protein kinase G.
Key words: nitric oxide; soluble guanylyl cyclase; protein kinase G; cGMP; caspase; apoptosis; PC12
Copyright © 1999 Society for Neuroscience 0270-6474/99/19166740-08$05.00/0
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