Nitric oxide mitigates apoptosis in human endothelial cells induced by 9,10-phenanthrenequinone: role of proteasomal function.
It has been widely recognized that nitric oxide (NO) suppresses oxidative damage of endothelial cell, but little is known about its pathophysiological role in apoptotic induction by 9,10-phenanthrenequinone (9,10-PQ), a major quinone component in diesel exhaust particles. Here, we have investigated the change in NO level in human aortic endothelial cells and the effect of NO in each step of apoptotic signaling initiated by 9,10-PQ. Treatment with 9,10-PQ evoked a bell-shaped production of NO, which was presumably due to increase in an active form of endothelial NO synthase. Pretreatment with exogenous NO decreased the susceptibility of the cells to 9,10-PQ, and retrieved from apoptotic signaling (reactive oxygen species generation, glutathione depletion and caspase activation) induced during exposure to high concentrations of 9,10-PQ. In addition, inhibition of endogenous NO production augmented the toxicity of 9,10-PQ. Interestingly, the 9,10-PQ treatment resulted in marked decreases in the proteasomal activities, which were partially abrogated by NO and a cell-permeable cGMP analog. These results indicate that proteasomal dysfunction by oxidative stress participates in the 9,10-PQ-induced apoptotic signaling and is ameliorated by NO via a cGMP-dependent pathway, thereby suggesting the protective role of NO in vascular damage caused by 9,10-PQ.
Matsunaga
Toshiyuki
T
Laboratory of Biochemistry, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan. matsunagat@gifu-pu.ac.jp
Arakaki
Marina
M
Kamiya
Tetsuro
T
Haga
Mariko
M
Endo
Satoshi
S
El-Kabbani
Ossama
O
Hara
Akira
A
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009153:Mutagens / Q000633:toxicity*; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D018384:Oxidative Stress / Q000187:drug effects; D010616:Phenanthrenes / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects*
D004791:Enzyme Inhibitors; D009153:Mutagens; D020030:Nitric Oxide Donors; D010616:Phenanthrenes; D009569:Nitric Oxide; C005399:9,10-phenanthrenequinone; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D046988:Proteasome Endopeptidase Complex; D006162:Guanylate Cyclase; D005978:Glutathione