Metabolic Fate of Peroxynitrite in Aqueous Solution

Pfeiffer, Silvia; Gorren, Antonius C.F.; Schmidt, Kurt; Werner, Ernst R.; Hansert, Bernhard; Bohle, D. Scott; Mayer, Bernd

doi:10.1074/jbc.272.6.3465

Cited by 299 publications

(183 citation statements)

References 48 publications

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“…Our data are consistent with a direct reaction between ⅐ NO and peroxynitrite. In support of this, ⅐ NO was shown to react with peroxynitrite, with a rate constant of 9.1 ϫ 10 4 M Ϫ1 s Ϫ1 (40).…”

Section: Discussionmentioning

confidence: 98%

The Effect of Nitric Oxide Release Rates on the Oxidation of Human Low Density Lipoprotein

Goss

Hogg

Kalyanaraman

1997

Journal of Biological Chemistry

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1-Substituted diazen-1-ium-1,2-diolates, a class of nitric oxide ( ⅐ NO) donor compounds that spontaneously release ⅐ NO at different rates, were used to investigate the effect of ⅐ NO release rate upon the oxidation of low density lipoprotein (LDL). All donor compounds conferred an inhibitory effect upon the oxidation of LDL; however, the effect exhibited a biphasic dependence upon the rate of ⅐ NO release. The ⅐ NO release rate that maximally inhibited oxidation was dependent upon the rate of oxidation. When LDL was rapidly oxidized by copper(II) sulfate, a faster release rate was more effective. In contrast, when LDL was oxidized slowly by 2,2 -azobis-2-amidinopropane hydrochloride, a slower release rate was most effective. This biphasic relationship between ⅐ NO release rate and the duration of inhibition was also demonstrated when LDL oxidation was initiated with 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium, a peroxynitrite generator. We conclude that the antioxidant ability of ⅐ NO is dependent not only upon the rate of its release from ⅐ NO donors, but also upon the rate of oxidation. This conclusion is supported by a kinetic model of LDL oxidation in the presence of ⅐ NO.The chronic inhibition of nitric oxide synthase (NOS) 1 accelerates atherosclerosis in cholesterol-fed rabbits (1, 2). Supplementation of L-arginine, the substrate for NOS, has been shown to decrease fatty streak formation in rabbits and correct endothelial dysfunction in hypercholesterolemic humans (3-5). These data suggest that basal production of ⅐ NO from the vascular endothelium can suppress the changes associated with early atherosclerotic lesion formation. Moreover, augmentation of ⅐ NO production can partially counteract the effects of elevated cholesterol levels.The mechanisms by which ⅐ NO affects atherosclerotic lesion formation are unclear; however, there are many possibilities.⅐ NO has been shown to inhibit inflammatory cell adhesion to the endothelium (6) and suppress smooth muscle cell proliferation (7). In later stages of atherosclerosis, the anti-thrombolytic properties of ⅐ NO (8) may also be relevant.It has frequently been proposed that the initiation of the atherosclerotic process is oxidative in nature. Free radicalmediated oxidative damage to both the vascular endothelium and low density lipoprotein (LDL) has been proposed to be a vital component of the atherosclerotic mechanism (9, 10). We have recently shown that ⅐ NO suppresses the oxidative modification of LDL (11-13) and inhibits the toxicity of oxidized LDL to endothelial cells (14). We have proposed that the way in which ⅐ NO inhibits oxidative processes is by scavenging propagatory lipid peroxyl radicals, thus suppressing the lipid peroxidation chain reaction (11)(12)(13)(14). This mechanism will generate lipid/NO adducts that have recently been identified (15,16).Many biological effects of ⅐ NO appear to be related to the rate of ⅐ NO formation (15,17,18). Bolus delivery of high concentrations of ⅐ NO may result in limited LDL oxidation that can be augmente...

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Section: Discussionmentioning

confidence: 98%

The Effect of Nitric Oxide Release Rates on the Oxidation of Human Low Density Lipoprotein

Goss

Hogg

Kalyanaraman

1997

Journal of Biological Chemistry

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“…(i) The decomposition of peroxynitrite in acidic solutions yields nitrate as a final product, but as the pH is raised, O 2 and nitrite in a 1:2 ratio are formed at the expense of nitrate, reaching ca. 40% O 2 at pH 9 (12,13). (ii) The decomposition of peroxynitrite in the presence of bicarbonate yields nitrate as a final product at all pH levels (28).…”

Section: Discussionmentioning

confidence: 99%

“…Additional insight gained during these later investigations allowed the pH dependence of the product yield of peroxynitrite decomposition to be explained, i.e., the decomposition of peroxynitrite in acidic solutions yields nitrate as a final product, but as the pH is raised, O 2 and nitrite in a 1:2 ratio are formed at the expense of nitrate, reaching ca. 40% O 2 at pH 9 (12,13). The slowly returning faith in the radical model was disturbed recently by Khan et al (14), who reported that the decomposition of peroxynitrite at neutral pH forms high yields of NO Ϫ and 1 O 2 .…”

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confidence: 98%

The decomposition of peroxynitrite does not yield nitroxyl anion and singlet oxygen

Merényi

Lind²,

Czapski³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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In a recent article [Khan, A. U., Kovacic, D., Kolbanovsky, A., Desai, M., Frenkel, K. & Geacintov, N. E. (2000) Proc. Natl. Acad. Sci. USA 97, 2984 -2989], the authors claimed that ONOO ؊ , after protonation to ONOOH, decomposes into 1 HNO and 1 O2 according to a spin-conserved unimolecular mechanism. This claim was based partially on their observation that nitrosylhemoglobin is formed via the reaction of peroxynitrite with methemoglobin at neutral pH. However, thermochemical considerations show that the yields of 1 O2 and 1 HNO are about 23 orders of magnitude lower than those of ⅐ NO2 and ⅐ OH, which are formed via the homolysis of ONOOH. We also show that methemoglobin does not form with peroxynitrite any spectrally detectable product, but with contaminations of nitrite and H 2O2 present in the peroxynitrite sample. Thus, there is no need to modify the present view of the mechanism of ONOOH decomposition, according to which initial homolysis into a radical pair, [ONO ⅐ ⅐ OH] cage, is followed by the diffusion of about 30% of the radicals out of the cage, while the rest recombines to nitric acid in the solvent cage.A lthough Mahoney (1) had demonstrated as early as in 1970 that the decomposition of ONOOH yields about 30% ⅐ NO 2 and ⅐ OH free radicals, a great confusion ensued during the next two decades because of misinterpretations of inconclusive experiments, sometimes stimulated by improper thermodynamic estimations (2-7). Fortunately, by the end of the nineties, the radical mechanism was readopted after judicious experiments in several laboratories (8-11). Additional insight gained during these later investigations allowed the pH dependence of the product yield of peroxynitrite decomposition to be explained, i.e., the decomposition of peroxynitrite in acidic solutions yields nitrate as a final product, but as the pH is raised, O 2 and nitrite in a 1:2 ratio are formed at the expense of nitrate, reaching ca. 40% O 2 at pH 9 (12, 13). The slowly returning faith in the radical model was disturbed recently by Khan et al. (14), who reported that the decomposition of peroxynitrite at neutral pH forms high yields of NO Ϫ and 1 O 2 . In this work, the authors claim that nitrosylhemoglobin (HbNO) is formed via the reaction of peroxynitrite with methemoglobin (MetHb) at neutral pH. They also report that the decomposition of peroxynitrite in the presence of 9,10-diphenylanthracene (DPA) forms substantial amounts of the transannular peroxide of DPA. Because DPA is considered a specific reagent for Materials and MethodsMaterials. All chemicals were of analytical grade and were used as received. Solutions were prepared with distilled water, which was purified further by using a Milli-Q water purification system from Millipore. Bovine MetHb (Sigma) was purified by passing through a Sephadex G-25 column and using 100 mM phosphate buffer (pH 7) as the eluant. The concentration of MetHb was determined from its absorption at 406 nm by using ϭ 154 mM Ϫ1 ⅐cm Ϫ1 (15). Fresh solutions of peroxynitrite were prepared before use ...

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“…NO synthesis was quantified as nitrite/nitrate formation by the Griess assay according to published procedures (25) in 96-well microplates with an Anthos HT3 microplate reader (Fresenius Kabi, Linz, Austria). Calibration curves were constructed with NaNO 2 .…”

Section: Methodsmentioning

confidence: 99%

Single-turnover of Nitric-oxide Synthase in the Presence of 4-Amino-tetrahydrobiopterin

Sørlie

Gorren

Marchal

et al. 2003

Journal of Biological Chemistry

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Tetrahydrobiopterin (BH4) is an essential cofactor of nitric-oxide synthase (NOS) that serves as a one-electron donor to the oxyferrous⅐heme complex. 4-Aminotetrahydrobiopterin (4-amino-BH4) is a potent inhibitor of NO synthesis, although it mimics all allosteric and structural effects of BH4 and exhibits comparable redox properties. We studied the reaction of reduced endothelial NOS oxygenase domain with O 2 in the presence of 4-amino-BH4 at ؊30°C by optical and electron paramagnetic resonance (EPR) spectroscopy. With Arg as the substrate, we observed a trihydropteridine radical with a corresponding heme species that was oxyferrous, with a Soret maximum at 428 nm and no EPR signal. With N G -hydroxy-L-arginine (NHA) no pterin radical appeared, whereas an axial ferrous heme⅐NO complex was formed. The corresponding optical spectra, with Soret bands at 417/423 nm, suggest that the proximal sulfur ligand is protonated. Accordingly, 4-amino-BH4 serves as a one-electron donor to Fe(II)⅐O 2 with both Arg and NHA, but the reaction cycle cannot be completed with either substrate. We propose that protonation of Fe(II)O 2 ؊ is inhibited in the presence of 4-amino-BH4. With Arg, dissociation of O 2 ؊ and binding of O 2 yields Fe(II)⅐O 2 and a pteridine radical; with NHA, reaction of the substrate with heme-bound O 2 ؊ eventually yields Fe(II)⅐NO and reduced 4-amino-BH4. These results suggest that BH4 donates a proton to Fe(II)⅐O 2 ؊ during catalysis and that inhibition by 4-amino-BH4 may be due to its inability to support this essential protonation step.

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Metabolic Fate of Peroxynitrite in Aqueous Solution

Cited by 299 publications

References 48 publications

The Effect of Nitric Oxide Release Rates on the Oxidation of Human Low Density Lipoprotein

The Effect of Nitric Oxide Release Rates on the Oxidation of Human Low Density Lipoprotein

The decomposition of peroxynitrite does not yield nitroxyl anion and singlet oxygen

Single-turnover of Nitric-oxide Synthase in the Presence of 4-Amino-tetrahydrobiopterin

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