Induction of heme oxygenase 1 by nitrosative stress

被引:101
作者
Naughton, P [1 ]
Foresti, R [1 ]
Bains, SK [1 ]
Hoque, M [1 ]
Green, CJ [1 ]
Motterlini, R [1 ]
机构
[1] Northwick Pk Inst Med Res, Dept Surg Res, Vasc Biol Unit, Harrow HA1 3UJ, Middx, England
关键词
D O I
10.1074/jbc.M203863200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Nitric oxide and S-nitrosothiols modulate a variety of important physiological activities. In vascular cells, agents that release NO and donate nitrosonium cation (NO+), such as S-nitrosoglutathione, are potent inducers of the antioxidant protein heme oxygenase 1 (HO-1) (Foresti, R., Clark, J. E., Green, C. J., and Motterlini, R. (1997) J. BioL Chem. 272, 18411-18417; Motterlini, R., Foresti, R., Bassi, R., Calabrese, V., Clark, J. E., and Green, C. J. (2000) J. BioL Chem. 275,13613-13620). Here, we report that Angeli's salt (AS) (0.25-2 mm), a compound that releases nitroxyl anion (NO-) at physiological pH, induces HO-1 mRNA and protein expression in a concentration- and time-dependent manner, resulting in increased heme oxygenase activity in rat H9c2 cells. A time course analysis revealed that NO--mediated HO-1 expression is transient and gradually disappears within 24 h, in accordance with the short half-life of AS at 37 degreesC (t(1/2) = 2.3 min). Interestingly, multiple additions of AS at lower concentrations (50 or 100 mum) over a period of time still promoted a significant increase in heme oxygenase activity. Experiments performed using a NO scavenger and the NO electrode confirmed that NO-, not NO, is the species involved in HO-1 induction by AS; however, the effect on heme oxygenase activity can be amplified by accelerating the rate of NO- oxidation. N-Acetylcysteine almost completely abolished AS-mediated induction of HO-1, whereas a glutathione synthesis inhibitor (buthionine sulfoximine) significantly decreased heme oxygenase activation by AS, indicating that sulfydryl groups are crucial targets in the regulation of HO-1 expression by NO-. We conclude that NO-, in analogy with other reactive nitrogen species, is a potent inducer of heme oxygenase activity and HO-1 protein expression. These findings indicate that heme oxygenase can act both as a sensor to and target of redox-based mechanisms involving NO and extend our knowledge on the biological function of HO-1 in response to nitrosative stress.
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收藏
页码:40666 / 40674
页数:9
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