Nitric oxide/cGMP signaling pathway protects RAW264 cells against nitric oxide-induced apoptosis by inhibiting the activation of p38 mitogen-activated protein kinase.
Nitric oxide (NO) induces apoptosis in various cells lines, while activation of the NO/cGMP signaling pathway prevents apoptosis induced by diverse stimuli, including NO. Here, we report the cytoprotective mechanisms of the NO/cGMP signaling pathway against NO-induced apoptosis in a mouse macrophage-like cell line, RAW264. Treatment with sodium nitroprusside (SNP), an NO donor, at a high-toxic concentration (4 mM) stimulated the N-terminal conformational change of Bax and its translocation to mitochondria followed by cytochrome c release and nuclear fragmentation in RAW264 cells. These changes of Bax were attenuated by pretreatment with SNP at a low-nontoxic concentration (100 microM) or dibutyryl cGMP (DBcGMP), a cell-permeable cGMP analogue. SB203580, a p38 mitogen-activated protein kinase (MAP kinase) inhibitor, blocked the effects of 4 mM SNP on Bax translocation and cell viability. Treatment with 4 mM SNP activated p38 MAP kinase and this effect was prevented by pretreatment with 100 microM SNP or DBcGMP. These findings suggest that the NO/cGMP signaling pathway inhibits NO-induced apoptosis of macrophages by suppressing the p38 MAP kinase activation, which results in N-terminal conformational change of Bax and its translocation to mitochondria.
Yoshioka
Yasuhiro
Y
Department of Pharmacotherapeutics, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan.
Yamamuro
Akiko
A
Maeda
Sadaaki
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D006152:Cyclic GMP / Q000378:metabolism*; D004789:Enzyme Activation; D008264:Macrophages / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D048051:p38 Mitogen-Activated Protein Kinases; D006152:Cyclic GMP