Inhibition of actin polymerization by peroxynitrite modulates neutrophil functional responses

Clements, Mark K.; Siemsen, Daniel W.; Swain, Steve D.; Hanson, Angela J.; Nelson-Overton, Laura K.; Rohn, Troy T.; Quinn, Mark T.

doi:10.1189/jlb.0802401

Cited by 56 publications

(48 citation statements)

References 78 publications

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“…Nitration seems to stabilize interactions between the pointed end of G-actin and the barbed ends of filaments that may stabilize formation of actin nuclei, accelerate filament elongation, and/or slow subunit dissociation. Actin nitration compromises several neutrophil functions (68). Nitrosylation of the four cysteine moieties closest to the carboxyl terminus clearly effects actin polymerization in several ways (Table 3).…”

Section: Discussionmentioning

confidence: 99%

Actin S-Nitrosylation Inhibits Neutrophil β2 Integrin Function

Thom

Bhopale

Mancini

et al. 2008

Journal of Biological Chemistry

117

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The focus of this work was to elucidate the mechanism for inhibition of neutrophil ␤ 2 integrin adhesion molecules by hyperoxia. Results demonstrate that exposure to high oxygen partial pressures increases synthesis of reactive species derived from type 2 nitric-oxide synthase and myeloperoxidase, leading to excessive S-nitrosylation of ␤-actin and possibly profilin. Hyperoxia causes S-nitrosylation of the four cysteine moieties closest to the carboxyl-terminal end of actin, which results in formation of short actin filaments. This alters actin polymerization, network formation, and intracellular distribution, as well as inhibits ␤ 2 integrin clustering. If neutrophils are exposed to ultraviolet light to reverse S-nitrosylation, or are incubated with N-formyl-methionyl-leucine-phenylalanine to trigger "insideout" activation, the effects of hyperoxia are reversed. We conclude that cytoskeletal changes triggered by hyperoxia inhibit ␤ 2 integrin-dependent neutrophil adhesion.

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Section: Discussionmentioning

confidence: 99%

Actin S-Nitrosylation Inhibits Neutrophil β2 Integrin Function

Thom

Bhopale

Mancini

et al. 2008

Journal of Biological Chemistry

117

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“…Its organization in filaments is fundamental for its function. Oxidation and in particular nitration of actin can alter actin polymerization (47). The motor neuron, with its extensive network of cell processes, needs a particularly efficient transport system to transfer cellular components synthesized in the cell body to their correct destination.…”

Section: Fig 3 Nt Immunoreactivity In Ventral Horn Of Transverse Sementioning

confidence: 99%

Protein Nitration in a Mouse Model of Familial Amyotrophic Lateral Sclerosis

Casoni

Basso

Massignan

et al. 2005

Journal of Biological Chemistry

173

119

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Multiple mechanisms have been proposed to contribute to amyotrophic lateral sclerosis (ALS) pathogenesis, including oxidative stress. Early evidence of a role for oxidative damage was based on the finding, in patients and murine models, of high levels of markers, such as free nitrotyrosine (NT). However, no comprehensive study on the protein targets of nitration in ALS has been reported. We found an increased level of NT immunoreactivity in spinal cord protein extracts of a transgenic mouse model of familial ALS (FALS) at a presymptomatic stage of the disease compared with age-matched controls. NT immunoreactivity is increased in the soluble fraction of spinal cord homogenates and is found as a punctate staining in motor neuron perikarya of presymptomatic FALS mice. Using a proteome-based strategy, we identified proteins nitrated in vivo, under physiological or pathological conditions, and compared their level of specific nitration. ␣-and ␥-enolase, ATP synthase ␤ chain, and heat shock cognate 71-kDa protein and actin were overnitrated in presymptomatic FALS mice. We identified by matrix-assisted laser desorption/ionization mass spectrometry 16 sites of nitration in proteins oxidized in vivo. In particular, ␣-enolase nitration at Tyr 43 , target also of phosphorylation, brings additional evidence on the possible interference of nitration with phosphorylation. In conclusion, we propose that protein nitration may have a role in ALS pathogenesis, acting directly by inhibiting the function of specific proteins and indirectly interfering with protein degradation pathways and phosphorylation cascades.

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“…On the other hand, it has been shown that Cys 374 of actin monomer (G-actin) is particularly sensitive to oxidation by hydrogen peroxide [3] and nitric oxide donors [4], which are stress conditions leading to a reduction of the actin polymer (F-actin), that plays a major role in myofibril contraction. Peroxynitrite is an important oxidative stress agent in ischemia/reperfusion insults, such as heart infarct or atrial fibrillation [1,5,6], and inflammation [7], and it has been reported that peroxynitrite can inhibit actin polymerization in neutrophils [8]. Furthermore, in aged muscle, actin is one of the proteins showing higher content of the commonly used fingerprint marker of peroxynitrite-reactive proteins 3-nitrotyrosine [9].…”

Section: Introductionmentioning

confidence: 99%

Peroxynitrite induces F-actin depolymerization and blockade of myosin ATPase stimulation

Tiago

Ramos

Aureliano

et al. 2006

Biochemical and Biophysical Research Communications

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Treatment of F-actin with the peroxynitrite-releasing agent 3-morpholinosydnonimine (SIN-1) produced a dose-dependent F-actin depolymerization. This is due to released peroxynitrite because it is not produced by 'decomposed SIN-1', and it is prevented by superoxide dismutase concentrations efficiently preventing peroxynitrite formation. F-actin depolymerization has been found to be very sensitive to peroxynitrite, as exposure to fluxes as low as 50-100 nM peroxynitrite leads to nearly 50% depolymerization in about 1 h. G-actin polymerization is also impaired by peroxynitrite although with nearly 2-fold lower sensitivity. Exposure of F-actin to submicromolar fluxes of peroxynitrite produced cysteine oxidation and also a blockade of the ability of actin to stimulate myosin ATPase activity. Our results suggest that an imbalance of the F-actin/G-actin equilibrium can account for the observed structural and functional impairment of myofibrils under the peroxynitrite-mediated oxidative stress reported for some pathophysiological conditions. Ó 2006 Elsevier Inc. All rights reserved.Keywords: F-actin; Peroxynitrite; Myosin ATPase; Actin polymerization/depolymerization; Oxidative stress; SIN-1; Cysteine oxidation Exposure of muscle cells to chronic oxidative stress conditions results in impairment of muscle contraction, which has been proposed to be, at least in part, the result of oxidative modification of myofibril proteins [1,2]. On the other hand, it has been shown that Cys 374 of actin monomer (G-actin) is particularly sensitive to oxidation by hydrogen peroxide [3] and nitric oxide donors [4], which are stress conditions leading to a reduction of the actin polymer (F-actin), that plays a major role in myofibril contraction. Peroxynitrite is an important oxidative stress agent in ischemia/reperfusion insults, such as heart infarct or atrial fibrillation [1,5,6], and inflammation [7], and it has been reported that peroxynitrite can inhibit actin polymerization in neutrophils [8]. Furthermore, in aged muscle, actin is one of the proteins showing higher content of the commonly used fingerprint marker of peroxynitrite-reactive proteins 3-nitrotyrosine [9]. During inflammation and ischemia/reperfusion episodes tissue cells are exposed to fluxes of peroxynitrite ranging from submicromolar to micromolar concentrations [7,10]. SIN-1 is being used to mimic the effects of chronic exposure of cells in culture to a peroxynitrite oxidative stress [11,12], because it slowly decomposes in neutral and weakly alkaline aqueous solutions releasing nitric oxide and superoxide anion [13], which react with each other to produce peroxynitrite with a second order rate constant of (4-7) · 10 9 M À1 s À1 close to the diffusion limit for chemical reactions [10,14]. Moreover, the kinetics of peroxynitrite generation and the peroxynitrite concentration attained in the solution during SIN-1 decomposition can be reliably monitored in the buffered solutions commonly used for biochemical studies with isolated subcellular components [15]. 0 ...

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Inhibition of actin polymerization by peroxynitrite modulates neutrophil functional responses

Cited by 56 publications

References 78 publications

Actin S-Nitrosylation Inhibits Neutrophil β2 Integrin Function

Actin S-Nitrosylation Inhibits Neutrophil β2 Integrin Function

Protein Nitration in a Mouse Model of Familial Amyotrophic Lateral Sclerosis

Peroxynitrite induces F-actin depolymerization and blockade of myosin ATPase stimulation

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