Nitric Oxide and Intracellular Heme

Kim, Yong-Mi; Bergonia, HA; Müller, Cláudia; Br, Pitt; Wd, Watkins; Lancaster,

doi:10.1016/s1054-3589(08)61092-3

Cited by 44 publications

(31 citation statements)

References 70 publications

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“…We have shown recently that one effect of endogenous • NO synthesis in isolated rat hepatocytes is upregulation of the heat shock protein hsp32, heme oxygenase (HO), as a result of nitrogen oxide-induced liberation of enzyme-bound (primarily cytochrome P450) heme [20,21]. We were thus interested to know whether HO may play a role in SNAP-induced induction of an autoprotective response.…”

Section: Resultsmentioning

confidence: 99%

“…This indicates that nitrogen oxide exposure induces resistance to injury from both reactive nitrogen and reactive oxygen species. We have previously shown that endogenous or exogenous nitrogen oxide exposure induces modest but significant increase in cytosolic non-heme iron [20,21]. Increased cytosolic iron is known to upregulate the synthesis of ferritin, which may be an important protective response against oxidative injury by sequestering iron and thus preventing the formation of hydroxyl radical via the Fenton reaction [27].…”

Section: Resultsmentioning

confidence: 99%

“…We have shown previously that *NO upregulates hsp32 (heme oxygenase-1; HO-1) via liberation of intracellular heme [20] and suggested that this may be a protective response [21]. Welsh and Sandler have shown induction of H• mRNA and protection against *NO toxicity by addition of heme [28], although exogenous heme addition could protect by directly scavenging •NO.…”

Section: Discussionmentioning

confidence: 99%

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Nitrogen oxide‐induced autoprotection in isolated rat hepatocytes

Kim

Bergonia

Lancaster³

1995

FEBS Letters

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197

110

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Pretreatment of rat hepatocytes with low-dose nitrogen oxide (addition of SNAP in vitro or induction of nitric oxide synthase in vitro or in vivo) imparts resistance to killing and decrease in aconitase and mitochondrial electron transfer from a second exposure to a higher dose of SNAP. Induction of this resistance is prevented by cycloheximide, indicating upregulation of protective protein(s). Ferritin levels are increased as are nonheme iron-NO EPR signals. Tin-protoporphyrin (SnPP) prevents protection, suggesting involvement of hsp32 (heme oxygenase) and/or guanylyl cyclase (GC). Cross-resistance to H2Oz killing is also observed, which is also prevented by cycloheximide and SnPP. Thus, hepatocytes possess inducible protective mechanisms against nitrogen oxide and reactive oxygen toxicity.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Nitrogen oxide‐induced autoprotection in isolated rat hepatocytes

Kim

Bergonia

Lancaster³

1995

FEBS Letters

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197

110

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“…Chronic NO exposure has been shown to result in liberation of prosthetic heme (53). This mobilization of heme in the cell could easily serve as a catalyst for NT formation in the presence of H 2 O 2 and NO 2 Ϫ derived from NO (Fig.…”

Section: Discussionmentioning

confidence: 99%

Protein nitration is mediated by heme and free metals through Fenton-type chemistry: An alternative to the NO/O\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\setlength{\oddsidemargin}{-69pt}\begin{document}\begin{equation}{\mathrm{_{2}^{-}}}\end{equation}\end{document} reaction

Thomas

Espey

Vitek

et al. 2002

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

176

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The chemical origins of nitrated tyrosine residues (NT) formed in proteins during a variety of pathophysiological conditions remain controversial. Although numerous studies have concluded that NT is a signature for peroxynitrite (ONOO ؊ ) formation, other works suggest the primary involvement of peroxidases. Because metal homeostasis is often disrupted in conditions bearing NT, the role of metals as catalysts for protein nitration was examined. nitrotyrosine ͉ nitric oxide ͉ peroxynitrite ͉ oxidation ͉ hemin N itrated tyrosine residues (NT) have been used as a marker of the involvement of nitric oxide (NO) and its related chemistry in a number of pathophysiological disorders including cardiovascular (1, 2) neurodegenerative and malignant conditions (1-5), such as septic shock (6), multiple sclerosis (7), Alzheimer's disease (8), and amyotrophic lateral sclerosis (9). In cancer the presence of NT often correlates with a poor prognosis (10), suggesting diagnostic implications.Several mechanisms for NT formation have been proposed, and its origin remains controversial (11-16). Detection of NT in vitro following exposure to synthetic peroxynitrite (ONOO Ϫ ) initially suggested that the reaction of NO with superoxide (O 2 Ϫ ) may be the primary source of NT (17,18). Further studies demonstrated that cogeneration of NO and O 2 Ϫ gave dissimilar results than bolus synthetic ONOO Ϫ (12,19,20). These disparities in nitration yields arose from further reactions of ONOO Ϫ with excess NO or O 2 Ϫ (21). Given the complexity of this seemingly simple reaction, much debate has ensued over the likelihood of NT formation under biologically relevant conditions (12,14).In addition to a ONOO Ϫ -mediated pathway, NT formation has been shown to result from the catalysis of nitrite oxidation by peroxidases, thus providing an alternate mechanism for its formation in vivo (22-24). Although leukocyte peroxidases likely account for a substantial amount of NT production in vivo, this mechanism fails to explain NT formation in the absence of inflammatory cells or peroxidases [i.e., a MPO Ϫ/Ϫ mouse model (25)].NT has been shown to occur on distinct proteins rather than in an indiscriminate manner (26). This may result from variations in protein susceptibility to nitration due to conformational differences or to association with redox active metals (27,28). We evaluated the relative efficacy of the synthetic ONOO Ϫ , NO͞O 2 Ϫ cogeneration, peroxidase, and redox active metal pathways to promote NT formation. Materials and MethodsBSA (essentially globulin-free), ribonuclease A, ferriprotoporphyrin IX (hemin), superoxide dismutase (SOD; bovine erythrocytes), cytochrome c, horseradish peroxidase (HRP), catalase (Cat), hypoxanthine (HX), myoglobin (horse heart), 2,2Ј-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), FeSO 4 , diethylenetriaminepentaacetic acid (DTPA), dimethylformamide (DMF), ␤-amyloid (1-42) protein (A␤), MnO 2 , and CuCl 2 were purchased from Sigma-Aldrich. H 2 O 2 , NaHCO 3 , NaNO 2 , and FeCl 3 were from Fisher Scientific....

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“…Like NO, carbon monoxide (CO) has also been identified as an endogenous second messenger in the peripheral and central nervous system, and has been demonstrated to play an important role in hemodynamic regulation (10,11). Both NO and CO have high affinity for both protein-bound and free heme-iron (12)(13)(14). Recently, the cytostatic activity of NO was found to correlate with NO-induced increase in eIF2␣ phosphorylation and inhibition of protein synthesis in a number of cell lines (15).…”

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confidence: 99%

The Heme-regulated Eukaryotic Initiation Factor 2α Kinase

Uma

Yun

Matts

2001

Journal of Biological Chemistry

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Nitric oxide (NO) has been reported to inhibit protein synthesis in eukaryotic cells by increasing the phosphorylation of the ␣-subunit of eukaryotic initiation factor (eIF) 2. However, the mechanism through which this increase occurs has not been characterized. In this report, we examined the effect of the diffusible gases nitric oxide (NO) and carbon monoxide (CO) on the activation of the heme-regulated eIF2␣ kinase (HRI) in rabbit reticulocyte lysate. Spectral analysis indicated that both NO and CO bind to the N-terminal heme-binding domain of HRI. Although NO was a very potent activator of HRI, CO markedly suppressed NO-induced HRI activation. The NO-induced activation of HRI was transduced through the interaction of NO with the N-terminal heme-binding domain of HRI and not through S-nitrosylation of HRI. We postulate that the regulation of HRI activity by diffusible gases may be of wider physiological significance, as we further demonstrate that NO generators increase eIF2␣ phosphorylation levels in NT2 neuroepithelial and C2C12 myoblast cells and activate HRI immunoadsorbed from extracts of these non-erythroid cell lines.Over 2 decades ago, the heme-regulated inhibitor (HRI) 1 of protein chain initiation in rabbit reticulocyte lysate (RRL) was identified as a heme-regulated protein kinase that phosphorylated the ␣-subunit of eukaryotic initiation factor eIF2 (reviewed in Refs. 1-3). eIF2 delivers Met-tRNA i in a complex with GTP to 43 S ribosomal initiation complexes and is released as a complex with GDP at the completion of the initiation cycle. Recycling of eIF2⅐GDP and the formation of eIF2⅐GTP⅐Met-tRNA i complexes requires the action of the guanine nucleotide exchange factor, eIF2B. Under heme-deficient conditions, HRI is activated and phosphorylates eIF2. Phosphorylated eIF2 avidly binds eIF2B, sequestering eIF2B in a poorly dissociable complex, which subsequently leads to the inhibition of the initiation of translation, as eIF2⅐GDP complexes that are present in excess of eIF2B fail to recycle. Thus, HRI functions to coordinate globin synthesis with heme availability in RRL.The amino acid sequence deduced from HRI cDNA indicates that it is composed of at least five distinct domains (4). The unique N-terminal domain of HRI contains ϳ165 amino acids. The second and fourth domains contain conserved sequence motifs I-V and motifs VI-XI, which comprise the N-terminal and C-terminal catalytic lobes of protein kinases, respectively. The third and fifth domains are also unique, consisting of ϳ140 amino acids that are inserted between the two conserved kinase lobes and ϳ50 amino acids at the C terminus, respectively.HRI is a hemoprotein that contains two distinct of hemebinding sites (5-7). Heme binding to the first site is stable, and remains associated with purified HRI, whereas heme-binding to the second site is reversible and appears to be responsible for the rapid heme-induced down-regulation of HRI activity . We have recently demonstrated that the N-terminal domain of HRI contains the stable heme-binding...

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Nitric Oxide and Intracellular Heme

Cited by 44 publications

References 70 publications

Nitrogen oxide‐induced autoprotection in isolated rat hepatocytes

Nitrogen oxide‐induced autoprotection in isolated rat hepatocytes

The Heme-regulated Eukaryotic Initiation Factor 2α Kinase

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