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Dinitrosyliron Complexes and the Mechanism(S) of Cellular Protein Nitrosothiol Formation from Nitric Oxide

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Dinitrosyliron Complexes and the Mechanism(S) of Cellular Protein Nitrosothiol Formation from Nitric Oxide Dinitrosyliron complexes and the mechanism(s) of cellular protein nitrosothiol formation from nitric oxide Charles A. Boswortha,b, Jose´ C. Toledo, Jr.c, Jaroslaw W. Zmijewskib,d, Qian Lib,e, and Jack R. Lancaster, Jr.a,b,e,f,1 Departments of aPhysiology and Biophysics, dMedicine, eAnesthesiology, and fEnvironmental Health Sciences, and bCenter for Free Radical Biology, University of Alabama, Birmingham, AL 35205; and cCentro de Cieˆncias Naturais e Humanas, Universidade Federal do ABC, CEP 09210-170, Santo Andre´, Sao Paulo, Brazil Edited by Louis J. Ignarro, University of California School of Medicine, Los Angeles, CA, and approved January 13, 2009 (received for review November 1, 2007) Nitrosothiols (RSNO), formed from thiols and metabolites of nitric presence of a cellular electron acceptor (6); reaction between •NO •Ϫ oxide (•NO), have been implicated in a diverse set of physiological and superoxide (O2 ) in the presence of excess •NO (7), and the and pathophysiological processes, although the exact mechanisms interaction between •NO and transition metals and/or metal- by which they are formed biologically are unknown. Several loproteins (8–14). candidate nitrosative pathways involve the reaction of •NO with In this study, we examine the contributions of potential nitrosa- O2, reactive oxygen species (ROS), and transition metals. We tive pathways in RAW 264.7 murine macrophages. We present developed a strategy using extracellular ferrocyanide to determine evidence suggesting that dinitrosyliron complexes (DNICs) formed that under our conditions intracellular protein RSNO formation at least in part from the cellular chelatable iron pool (CIP), through occurs from reaction of •NO inside the cell, as opposed to cellular an O2-independent transnitrosative process, are responsible for the entry of nitrosative reactants from the extracellular compartment. majority of RSNO formation in cells, and that reactive oxygen Using this method we found that in RAW 264.7 cells RSNO forma- species (ROS) enhance RSNO formation, possibly via increases in tion occurs only at very low (<8 ␮M) O2 concentrations and DNICs. exhibits zero-order dependence on •NO concentration. Indeed, RSNO formation is not inhibited even at O2 levels <1 ␮M. Addi- Results tionally, chelation of intracellular chelatable iron pool (CIP) reduces •NO Exposure Results in Intracellular RSNO Formation from Reactions RSNO formation by >50%. One possible metal-dependent, O2- of •NO Inside the Cell. Fig. 1A presents a scheme depicting our independent nitrosative pathway is the reaction of thiols with strategy for selectively detecting RSNO formation caused by intra- dinitrosyliron complexes (DNIC), which are formed in cells from the cellular reactions of free •NO. The presence of external ferrocya- reaction of •NO with the CIP. Under our conditions, DNIC forma- nide (FCN), which rapidly reacts with •NO2 (15), will prevent the tion, like RSNO formation, is inhibited by Ϸ50% after chelation of formation of nitrosative species in the external compartment, thus labile iron. Both DNIC and RSNO are also increased during over- preventing their entry into the cells. RAW 264.7 macrophages were production of ROS by the redox cycler 5,8-dimethoxy-1,4-naphtho- incubated 60 min with •NO donor [10 ␮M N-4–1-3-aminopropyl- quinone. Taken together, these data strongly suggest that cellular 2-hydroxy-2-nitrosohydrazinobutyl-1,3-propane-diamine (sper/ RSNO are formed from free •NO via transnitrosation from DNIC NO), t1/2 ϭ 39 min] with or without FCN (1 mM). Fig. 1B shows that derived from the CIP. We have examined in detail the kinetics and there is no statistical difference between intracellular RSNO for- mechanism of RSNO formation inside cells. mation with or without FCN. However, nitrosation of an extracel- lular target (BSA) was nearly completely inhibited (85.8 Ϯ 6.4%). iron ͉ nitrosation ͉ reactive nitrogen species ͉ reactive oxygen species ͉ These results indicate that under our conditions the RSNO formed chelatable iron inside the cell are primarily caused by the diffusion of •NO into the cell and reaction with cellular components. itric oxide (nitrogen monoxide, •NO) is a ubiquitous signaling Nmolecule that originally was thought to exert its effects solely Time Course of RSNO, •NO, and O2 Levels. To determine the effects through interaction with transition metal ligands of proteins, most of O2 on cellular RSNO formation, we measured RSNO and O2 in notably the heme group of soluble guanylate cyclase. However, it is cell suspensions exposed to •NO donor. Because of the dual effects now recognized that •NO is capable of affecting cell physiology by of •NO on O2 consumption (16) and O2 on •NO consumption (17) inducing oxidative and covalent modification of protein amino acid it is essential to also measure the •NO concentration because BIOCHEMISTRY residues. One such modification, S-nitrosation, the addition of a varying the concentration of one will necessarily affect the other. nitroso group to a thiol to form a nitrosothiol (RSNO), has received When cells are added in the presence of sper/NO, O2 levels rapidly ␮ Ϸ considerable attention as a potentially important posttranslational decline, reaching 8 Min 15 min, after which they decline slowly Ϸ ␮ protein modification. S-nitrosated products are found ubiquitously to 3 M at the end of the 60-min incubation (Fig. 2A). Subsequent in vivo (1), and thiol nitrosation has been found to alter the activity addition of dithionite results in immediate disappearance of O2, of a diverse set of proteins and may therefore represent an indicating that the •NO at these low O2 levels is inhibiting respi- important concept in cellular and organismal biology (2). A central issue in this paradigm is understanding the routes by Author contributions: C.A.B., J.C.T., J.W.Z., and J.R.L. designed research; C.A.B., J.C.T., which RSNO are formed inside cells. Importation of low molecular J.W.Z., and Q.L. performed research; C.A.B. and J.W.Z. contributed new reagents/analytic weight (LMW) RSNO through LAT transporters, followed by tools; C.A.B., J.C.T., J.W.Z., Q.L., and J.R.L. analyzed data; and C.A.B. and J.R.L. wrote the transnitrosation reactions, have been demonstrated to be a potent paper. route for intracellular RSNO formation (3). However, mechanisms The authors declare no conflict of interest. of de novo synthesis from free •NO are less clear. Proposed This article is a PNAS Direct Submission. mechanisms include the reaction of •NO with O2 (autoxidation), 1To whom correspondence should be addressed. E-mail: [email protected]. either in the aqueous phase (4) or in an accelerated manner in This article contains supporting information online at www.pnas.org/cgi/content/full/ hydrophobic phases (5); reaction of •NO with a thiol in the 0710416106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0710416106 PNAS ͉ March 24, 2009 ͉ vol. 106 ͉ no. 12 ͉ 4671–4676 Downloaded by guest on September 30, 2021 A A 200 10 0. .7 5 M) μ .5 0 150 ( 2 O M) 2.5 μ .0 0 ( 100 0 15 30 45 60 2 Time (min) O 50 0 0 10 20 30 40 50 60 70 iT me (min) 60 tnI racell lu ar Ex rt acellular BC.s.n 60 (added BSA) B 900 45 45 80 ) 30 30 60 600 ) 15 15 40 RSNO (nM) * 300 ( [NO] (nM) RSNO (pmol/mg) 0 0 ( 20 -FCN +FCN -FCN +FCN RSNO (pmol/mg) 0 0 Fig. 1. Formation of intracellular RSNO is not caused by the autoxidation of 0 10 20 30 40 50 60 •NO in the extracellular space. (A) Scheme of extracellular versus intracellular Time (min) nitrosative processes. External addition of FCN will prevent cellular nitrosation from entry of nitrosative species formed extracellularly from •NO autoxida- C tion, resulting in RSNO formation from only intracellular •NO. See Results for 60 details. (B) Cells were exposed to sper/NO (10 ␮M) Ϯ FCN (1 mM) for 60 min, and RSNO level in lysates was determined as described in Methods.(C) Same 45 as A except nitrosation of external BSA (0.075 mg/mL) was measured. n.s., not significant. *, P Ͻ 0.05 compared with control. 30 15 ration. Levels of •NO remain low (Ͻ 20 nM) during the first 20 min RSNO (pmol/mg) of incubation, and then begin rising as O2 declines to Ͻ5 ␮M (Fig. 0 2 A and B). The very low levels of detectable •NO during the initial 0 10 20 30 40 50 60 Time (min) 20 min, despite constant •NO release from the donor, can be attributed to O2-dependent •NO consumption as shown in several Fig. 2. Time course of RSNO formation and •NO and O2 concentrations. (A) cell types (17, 18). By the end of the 60-min incubation, •NO levels Cells were added to PBSD containing sper/NO (10 ␮M) and 1 mM FCN, and O2 are 771 Ϯ 141 nM. Despite ongoing •NO formation and rapid concentration was monitored. (Inset) Scale expansion showing the slow de- cellular consumption during the first 20 min, RSNO formation is crease in O2 at longer times. At arrow, sodium dithionite was added. Repre- sentative data from 2 experiments are shown. (B) Conditions as in A except at not observed during this time (Fig. 2B). The mechanism of O2- dependent •NO consumption by cells thus does not involve nitro- 0, 12, 24, 36, 48, and 60 min cells were removed and processed for RSNO content (■). In parallel experiments, aliquots were removed at the indicated sative chemistry. In addition, nitrosation is observed only when free time points and analyzed for •NO concentration (‚). (C) Cells were incubated •NO begins to appear. Subsequent to the appearance of •NO, the with sper/NO and FCN as in A for 60 min, after which oxymyoglobin (20 ␮M) instantaneous rate of RSNO formation is constant despite a steady was added to scavenge •NO.
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