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Caruso G, Fresta CG, Martinez-Becerra F, Antonio L, Johnson RT, de Campos RPS, Siegel JM, Wijesinghe MB, Lazzarino G, Lunte SM. Carnosine modulates nitric oxide in stimulated murine RAW 264.7 macrophages. Mol Cell Biochem 2017; 431:197-210. [PMID: 28290048 DOI: 10.1007/s11010-017-2991-3] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Accepted: 02/24/2017] [Indexed: 12/24/2022]
Abstract
Excess nitric oxide (NO) production occurs in several pathological states, including neurodegeneration, ischemia, and inflammation, and is generally accompanied by increased oxidative/nitrosative stress. Carnosine [β-alanine-histidine (β-Ala-His)] has been reported to decrease oxidative/nitrosative stress-associated cell damage by reducing the amount of NO produced. In this study, we evaluated the effect of carnosine on NO production by murine RAW 264.7 macrophages stimulated with lipopolysaccharides + interferon-γ. Intracellular NO and intracellular and extracellular nitrite were measured by microchip electrophoresis with laser-induced fluorescence and by the Griess assay, respectively. Results showed that carnosine causes an apparent suppression of total NO production by stimulated macrophages accompanied by an unexpected simultaneous drastic increase in its intracellular low toxicity endproduct, nitrite, with no inhibition of inducible nitric oxide synthase (iNOS). ESI-MS and NMR spectroscopy in a cell-free system showed the formation of multiple adducts (at different ratios) of carnosine-NO and carnosine-nitrite, involving both constituent amino acids (β-Ala and His) of carnosine, thus providing a possible mechanism for the changes in free NO and nitrite in the presence of carnosine. In stimulated macrophages, the addition of carnosine was also characterized by changes in the expression of macrophage activation markers and a decrease in the release of IL-6, suggesting that carnosine might alter M1/M2 macrophage ratio. These results provide evidence for previously unknown properties of carnosine that modulate the NO/nitrite ratio of stimulated macrophages. This modulation is also accompanied by changes in the release of pro-inflammatory molecules, and does not involve the inhibition of iNOS activity.
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Affiliation(s)
- Giuseppe Caruso
- Ralph N. Adams Institute for Bioanalytical Chemistry, University of Kansas, Lawrence, KS, USA.,Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA
| | - Claudia G Fresta
- Ralph N. Adams Institute for Bioanalytical Chemistry, University of Kansas, Lawrence, KS, USA.,Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA
| | - Francisco Martinez-Becerra
- Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA.,Immunology Core Laboratory of the Kansas Vaccine Institute, University of Kansas, Lawrence, KS, USA
| | - Lopalco Antonio
- Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA
| | - Ryan T Johnson
- Department of Chemistry, University of Kansas, Lawrence, KS, USA
| | - Richard P S de Campos
- Ralph N. Adams Institute for Bioanalytical Chemistry, University of Kansas, Lawrence, KS, USA.,Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA.,Department of Chemistry, State University of Campinas, Campinas, Brazil
| | - Joseph M Siegel
- Ralph N. Adams Institute for Bioanalytical Chemistry, University of Kansas, Lawrence, KS, USA.,Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA
| | - Manjula B Wijesinghe
- Ralph N. Adams Institute for Bioanalytical Chemistry, University of Kansas, Lawrence, KS, USA.,Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA
| | - Giuseppe Lazzarino
- Division of Medical Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
| | - Susan M Lunte
- Ralph N. Adams Institute for Bioanalytical Chemistry, University of Kansas, Lawrence, KS, USA. .,Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA. .,Department of Chemistry, University of Kansas, Lawrence, KS, USA.
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He N, Jia JJ, Li JH, Zhou YF, Lin BY, Peng YF, Chen JJ, Chen TC, Tong RL, Jiang L, Xie HY, Zhou L, Zheng SS. Remote ischemic perconditioning prevents liver transplantation-induced ischemia/reperfusion injury in rats: Role of ROS/RNS and eNOS. World J Gastroenterol 2017; 23:830-841. [PMID: 28223727 PMCID: PMC5296199 DOI: 10.3748/wjg.v23.i5.830] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2016] [Revised: 12/08/2016] [Accepted: 12/21/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the underlying mechanisms of the protective role of remote ischemic perconditioning (RIPerC) in rat liver transplantation.
METHODS Sprague-Dawley rats were subjected to sham, orthotopic liver transplantation (OLT), ischemic postconditioning (IPostC) or RIPerC. After 3 h reperfusion, blood samples were taken for measurement of alanine aminotransferase, aspartate aminotransferase, creatinine (Cr) and creatinine kinase-myocardial band (CK-MB). The liver lobes were harvested for the following measurements: reactive oxygen species (ROS), H2O2, mitochondrial membrane potential (ΔΨm) and total nitric oxide (NO). These measurements were determined using an ROS/H2O2, JC1 and Total NOx Assay Kit, respectively. Endothelial NO synthase (eNOS) was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and western blotting, and peroxynitrite was semi-quantified by western blotting of 3-nitrotyrosine.
RESULTS Compared with the OLT group, the grafts subjected to RIPerC showed significantly improved liver and remote organ functions (P < 0.05). ROS (P < 0.001) including H2O2 (P < 0.05) were largely elevated in the OLT group as compared with the sham group, and RIPerC (P < 0.05) reversed this trend. The collapse of ΔΨm induced by OLT ischemia/reperfusion (I/R) injury was significantly attenuated in the RIPerC group (P < 0.001). A marked increase of NO content and phosphoserine eNOS, both in protein and mRNA levels, was observed in liver graft of the RIPerC group as compared with the OLT group (P < 0.05). I/R-induced 3-nitrotyrosine content was significantly reduced in the RIPerC group as compared with the OLT group (P < 0.05). There were no significant differences between the RIPerC and IPostC groups for all the results except Cr. The Cr level was lower in the RIPerC group than in the IPostC group (P < 0.01).
CONCLUSION Liver graft protection by RIPerC is similar to or better than that of IPostC, and involves inhibition of oxidative stress and up-regulation of the PI3K/Akt/eNOS/NO pathway.
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Changes in plasma and urinary nitrite after birth in premature infants at risk for necrotizing enterocolitis. Pediatr Res 2016; 79:432-7. [PMID: 26539663 PMCID: PMC5219926 DOI: 10.1038/pr.2015.229] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 08/06/2015] [Indexed: 01/13/2023]
Abstract
BACKGROUND Plasma nitrite serves as a reservoir of nitric oxide (NO) bioactivity. Because nitrite ingestion is markedly lower in newborns than adults, we hypothesized plasma nitrite levels would be lower in newborns than in adults, and that infants diagnosed with necrotizing enterocolitis (NEC), a disease characterized by ischemia and bacterial invasion of intestinal walls, would have lower levels of circulating nitrite in the days prior to diagnosis. METHODS Single blood and urine samples were collected from 9 term infants and 12 adults, 72 preterm infants every 5 d for 3 wk, and from 13 lambs before and after cord occlusion. RESULTS Nitrite fell 50% relative to cord levels in the first day after birth; and within 15 min after cord occlusion in lambs. Urinary nitrite was higher in infants than adults. Plasma and urinary nitrite levels in infants who developed NEC were similar to those of preterm control infants on days 1 and 5, but significantly elevated at 15 and 20 d after birth. CONCLUSION Plasma nitrite falls dramatically at birth while newborn urinary nitrite levels are significantly greater than adults. Acute NEC is associated with elevated plasma and urinary nitrite levels.
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Rahat MA, Hemmerlein B. Macrophage-tumor cell interactions regulate the function of nitric oxide. Front Physiol 2013; 4:144. [PMID: 23785333 PMCID: PMC3684767 DOI: 10.3389/fphys.2013.00144] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2013] [Accepted: 05/29/2013] [Indexed: 12/12/2022] Open
Abstract
Tumor cell-macrophage interactions change as the tumor progresses, and the generation of nitric oxide (NO) by the inducible nitric oxide synthase (iNOS) plays a major role in this interplay. In early stages, macrophages employ their killing mechanisms, particularly the generation of high concentrations of NO and its derivative reactive nitrogen species (RNS) to initiate tumor cell apoptosis and destroy emerging transformed cells. If the tumor escapes the immune system and grows, macrophages that infiltrate it are reprogramed in situ by the tumor microenvironment. Low oxygen tensions (hypoxia) and immunosuppressive cytokines inhibit iNOS activity and lead to production of low amounts of NO/RNS, which are pro-angiogenic and support tumor growth and metastasis by inducing growth factors (e.g., VEGF) and matrix metalloproteinases (MMPs). We review here the different roles of NO/RNS in tumor progression and inhibition, and the mechanisms that regulate iNOS expression and NO production, highlighting the role of different subtypes of macrophages and the microenvironment. We finally claim that some tumor cells may become resistant to macrophage-induced death by increasing their expression of microRNA-146a (miR-146a), which leads to inhibition of iNOS translation. This implies that some cooperation between tumor cells and macrophages is required to induce tumor cell death, and that tumor cells may control their fate. Thus, in order to induce susceptibility of tumors cells to macrophage-induced death, we suggest a new therapeutic approach that couples manipulation of miR-146a levels in tumors with macrophage therapy, which relies on ex vivo stimulation of macrophages and their re-introduction to tumors.
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Affiliation(s)
- Michal A Rahat
- Department of Immunology, Immunology Research Unit, Carmel Medical Center and the Ruth and Bruce Rappaport Faculty of Medicine Technion, Haifa, Israel
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Milsom AB, Fernandez BO, Garcia-Saura MF, Rodriguez J, Feelisch M. Contributions of nitric oxide synthases, dietary nitrite/nitrate, and other sources to the formation of NO signaling products. Antioxid Redox Signal 2012; 17:422-32. [PMID: 22133018 PMCID: PMC3365358 DOI: 10.1089/ars.2011.4156] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
UNLABELLED Mice lacking all three nitric oxide synthase (NOS) genes remain viable even though deletion of the major downstream target of NO, soluble guanylyl cyclase, is associated with a dramatically shortened life expectancy. Moreover, findings of relatively normal flow responses in eNOS knockouts are generally attributed to compensatory mechanisms including upregulation of remaining NOS isoforms, but the alternative possibility that dietary nitrite/nitrate (NOx) may contribute to basal levels of NO signaling has never been investigated. AIM The aim of the present study was to examine how NO signaling products (nitrosated and nitrosylated proteins) and NO metabolites (nitrite, nitrate) are affected by single NOS deletions and whether dietary NOx plays a compensatory role in any deficiency. Specifically, we sought to ascertain whether profound alterations of these products arise upon genetic deletion of either NOS isoform, inhibition of all NOS activity, NOx restriction, or all of the above. RESULTS Our results indicate that while some significant changes do indeed occur, they are surprisingly moderate and compartmentalized to specific tissues. Unexpectedly, even after pharmacological inhibition of all NOSs and restriction of dietary NOx intake in eNOS knockout mice significant levels of NO-related products remain. Innovation/Conclusion: These findings suggest that a yet unidentified source of NO, unrelated to NOSs or dietary NOx, may be sustaining basal NO signaling in tissues. Given the significance of NO for redox regulation in health and disease, it would seem to be important to identify the nature of this additional source of NO products as it may offer new therapeutic avenues for correcting NO deficiencies.
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Affiliation(s)
- Alexandra B Milsom
- Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA
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6
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Cespuglio R, Amrouni D, Meiller A, Buguet A, Gautier-Sauvigné S. Nitric oxide in the regulation of the sleep-wake states. Sleep Med Rev 2012; 16:265-79. [PMID: 22406306 DOI: 10.1016/j.smrv.2012.01.006] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2011] [Revised: 01/19/2012] [Accepted: 01/20/2012] [Indexed: 12/22/2022]
Abstract
Nitric oxide (NO) production involves four different NO-synthases (NOSs) that are either constitutive (neuronal, nNOS; endothelial, eNOS; mitochondrial, mNOS) or inducible (iNOS) in nature. Three main processes regulate NO/NOSs output, i.e., the L-arginine/arginase substrate-competing system, the L-citrulline/arginosuccinate-recycling system and the asymmetric dimethyl-/monomethyl-L-arginine-inhibiting system. In adult animals, nNOS exhibits a dense innervation intermingled with pontine sleep structures. It is well established that the NO/nNOS production makes a key contribution to daily homeostatic sleep (slow-wave sleep, SWS; rapid eye movement sleep, REM sleep). In the basal hypothalamus, the NO/nNOS production further contributes to the REM sleep rebound that takes place after a sleep deprivation (SD). This production may also contribute to the sleep rebound that is associated with an immobilization stress (IS). In adult animals, throughout the SD time-course, an additional NO/iNOS production takes place in neurons. Such production mediates a transitory SD-related SWS rebound. A transitory NO/iNOS production is also part of the immune system. Such a production contributes to the SWS increase that accompanies inflammatory events and is ensured by microglial cells and astrocytes. Finally, with aging, the iNOS expression becomes permanent and the corresponding NO/iNOS production is important to ensure an adequate maintenance of REM sleep and, to a lesser extent, SWS. Despite such maintenance, aged animals, however, are not able to elicit a sleep rebound to deal with the challenge of SD or IS. Sleep regulatory processes in adult animals thus become impaired with age. Reduced iNOS expression during aging may contribute to accelerated senescence, as observed in senescence-accelerated mice (SAMP-8 mice).
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Affiliation(s)
- Raymond Cespuglio
- University of Lyon, Faculty of Medicine, Neurosciences Research Center of Lyon, 8 Avenue Rockefeller, F-69373 Lyon, France.
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Wynne BM, Labazi H, Tostes RC, Webb RC. Aorta from angiotensin II hypertensive mice exhibit preserved nitroxyl anion mediated relaxation responses. Pharmacol Res 2011; 65:41-7. [PMID: 21767645 DOI: 10.1016/j.phrs.2011.07.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2011] [Revised: 06/23/2011] [Accepted: 07/03/2011] [Indexed: 10/18/2022]
Abstract
Hypertension is a disorder affecting millions worldwide, and is a leading cause of death and debilitation in the United States. It is widely accepted that during hypertension and other cardiovascular diseases the vasculature exhibits endothelial dysfunction; a deficit in the relaxatory ability of the vessel, attributed to a lack of nitric oxide (NO) bioavailability. Recently, the one electron redox variant of NO, nitroxyl anion (NO(-)) has emerged as an endothelium-derived relaxing factor (EDRF) and a candidate for endothelium-derived hyperpolarizing factor (EDRF). NO(-) is thought to exist protonated (HNO) in vivo, which would make this species more resistant to scavenging. However, no studies have investigated the role of this redox species during hypertension, and whether the vasculature loses the ability to relax to HNO. Thus, we hypothesize that aorta from angiotensin II (AngII)-hypertensive mice will exhibit a preserved relaxation response to Angeli's Salt, an HNO donor. Male C57Bl6 mice, aged 12-14 weeks were implanted with mini-osmotic pumps containing AngII (90ng/min, 14 days plus high salt chow) or sham surgery. Aorta were excised, cleaned and used to perform functional studies in a myograph. We found that aorta from AngII-hypertensive mice exhibited a significant endothelial dysfunction as demonstrated by a decrease in acetylcholine (ACh)-mediated relaxation. However, vessels from hypertensive mice exhibited a preserved response to Angeli's Salt (AS), the HNO donor. To confirm that relaxation responses to HNO were maintained, concentration response curves (CRCs) to ACh were performed in the presence of scavengers to both NO and HNO (carboxy-PTIO and L-cys, resp.). We found that ACh-mediated relaxation responses were significantly decreased in aorta from sham and almost completely abolished in aorta from AngII-treated mice. Vessels incubated with l-cys exhibited a modest decrease in ACh-mediated relaxations responses. These data demonstrate that aorta from AngII-treated hypertensive mice exhibit a preserved relaxation response to AS, an HNO donor, regardless of a significant endothelial dysfunction.
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Affiliation(s)
- Brandi M Wynne
- Department of Physiology, Medical College of Georgia, Augusta, GA 30912, United States.
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8
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Serum metabolic profile in multiple sclerosis patients. Mult Scler Int 2011; 2011:167156. [PMID: 22096628 PMCID: PMC3196932 DOI: 10.1155/2011/167156] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2011] [Revised: 03/30/2011] [Accepted: 05/02/2011] [Indexed: 12/31/2022] Open
Abstract
Multiple sclerosis (MS) is a progressive demyelinating process considered as an autoimmune disease, although the causes of this pathology have not been yet fully established. Similarly to other neurodegenerations, MS is characterized by a series of biochemical changes affecting to different extent neuronal functions; great attention has been given to oxidative/nitrosative stress and to alterations in mitochondrial functions. According to previous data, MS patients show significant changes in the circulating concentrations of different metabolites, although it is still unclear whether uric acid undergoes to decrease, increase, or no change under this pathological condition. In this study, we report the serum metabolic profile in terms of purines, pyrimidines, creatinine, malondialdehyde, ascorbic acid, nitrite, and nitrate in a group of 170 MS patients. The results show increase in circulating uric acid and other oxypurines (hypoxanthine and xanthine), as well as in uridine and β-pseudouridine. The concomitant increase in circulating creatinine, malondialdehyde, nitrite, and nitrate, and decrease in ascorbic acid, demonstrates that MS induces alteration in energy metabolism and in oxidants/antioxidants balance that can be monitored in serum of MS patients.
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Signoretti S, Vagnozzi R, Tavazzi B, Lazzarino G. Biochemical and neurochemical sequelae following mild traumatic brain injury: summary of experimental data and clinical implications. Neurosurg Focus 2010; 29:E1. [PMID: 21039135 DOI: 10.3171/2010.9.focus10183] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Although numerous studies have been carried out to investigate the pathophysiology of mild traumatic brain injury (mTBI), there are still no standard criteria for the diagnosis and treatment of this peculiar condition. The dominant theory that diffuse axonal injury is the main neuropathological process behind mTBI is being revealed as weak at best or inconclusive, given the current literature and the fact that neuronal injury inherent to mTBI improves, with few lasting clinical sequelae in the vast majority of patients. Clinical and experimental evidence suggests that such a course, rather than being due to cell death, is based on temporal neuronal dysfunction, the inevitable consequence of complex biochemical and neurochemical cascade mechanisms directly and immediately triggered by the traumatic insult. This report is an attempt to summarize data from a long series of experiments conducted in the authors' laboratories and published during the past 12 years, together with an extensive analysis of the available literature, focused on understanding the biochemical damage produced by an mTBI. The overall clinical implications, as well as the metabolic nature of the post-mTBI brain vulnerability, are discussed. Finally, the application of proton MR spectroscopy as a possible tool to monitor the full recovery of brain metabolic functions is emphasized.
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Affiliation(s)
- Stefano Signoretti
- Department of Neurosciences Head and Neck Surgery, San Camillo Hospital, Rome, Italy.
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Comhair SAA, Erzurum SC. Redox control of asthma: molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal 2010; 12:93-124. [PMID: 19634987 PMCID: PMC2824520 DOI: 10.1089/ars.2008.2425] [Citation(s) in RCA: 185] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
An imbalance in reducing and oxidizing (redox) systems favoring a more oxidative environment is present in asthma and linked to the pathophysiology of the defining symptoms and signs including airflow limitation, hyper-reactivity, and airway remodeling. High levels of hydrogen peroxide, nitric oxide ((*)NO), and 15-F(2t)-isoprostane in exhaled breath, and excessive oxidative protein products in lung epithelial lining fluid, peripheral blood, and urine provide abundant evidence for pathologic oxidizing processes in asthma. Parallel studies document loss of reducing potential by nonenzymatic and enzymatic antioxidants. The essential first line antioxidant enzymes superoxide dismutases (SOD) and catalase are reduced in asthma as compared to healthy individuals, with lowest levels in those patients with the most severe asthma. Loss of SOD and catalase activity is related to oxidative modifications of the enzymes, while other antioxidant gene polymorphisms are linked to susceptibility to develop asthma. Monitoring of exhaled (*)NO has entered clinical practice because it is useful to optimize asthma care, and a wide array of other biochemical oxidative and nitrative biomarkers are currently being evaluated for asthma monitoring and phenotyping. Novel therapeutic strategies that target correction of redox abnormalities show promise for the treatment of asthma.
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Affiliation(s)
- Suzy A A Comhair
- Pathobiology, Lerner Research Institute, and the Respiratory Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
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11
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Flores-Santana W, Switzer C, Ridnour LA, Basudhar D, Mancardi D, Donzelli S, Thomas DD, Miranda KM, Fukuto JM, Wink DA. Comparing the chemical biology of NO and HNO. Arch Pharm Res 2009; 32:1139-53. [PMID: 19727606 DOI: 10.1007/s12272-009-1805-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2009] [Revised: 04/24/2009] [Accepted: 06/25/2009] [Indexed: 11/28/2022]
Abstract
For the past couple of decades nitric oxide (NO) and nitroxyl (HNO) have been extensively studied due to the important role they play in many physiological and/or pharmacological processes. Many researchers have reported important signaling pathways as well as mechanisms of action of these species, showing direct and indirect effects depending on the environment. Both NO and HNO can react with, among others, metals, proteins, thiols and heme proteins via unique and distinct chemistry leading to improvement of some clinical conditions. Understanding the basic chemistry of NO and HNO and distinguishing their mechanisms of action as well as methods of detection are crucial for understanding the current and potential clinical applications. In this review, we summarize some of the most important findings regarding NO and HNO chemistry, revealing some of the possible mechanisms of their beneficial actions.
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Affiliation(s)
- Wilmarie Flores-Santana
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Heikal L, Martin GP, Dailey LA. Characterisation of the decomposition behaviour of S-nitrosoglutathione and a new class of analogues: S-Nitrosophytochelatins. Nitric Oxide 2009; 20:157-65. [DOI: 10.1016/j.niox.2008.11.001] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2008] [Revised: 10/16/2008] [Accepted: 11/12/2008] [Indexed: 11/28/2022]
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Favaloro JL, Kemp-Harper BK. Redox variants of NO (NO{middle dot} and HNO) elicit vasorelaxation of resistance arteries via distinct mechanisms. Am J Physiol Heart Circ Physiol 2009; 296:H1274-80. [PMID: 19252101 DOI: 10.1152/ajpheart.00008.2009] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The free radical form of nitric oxide (NO(.)) is a well-known mediator of vascular tone. What is not so well recognized is that NO(.) exists in several different redox forms. There is considerable evidence that NO(.) and its one-electron reduction product, nitroxyl (HNO), have pharmacologically distinct actions that extend into the regulation of the vasculature. The aim of this study was to compare the vasorelaxation mechanisms of HNO and NO(.), including an examination of the ability of these redox variants to hyperpolarize and repolarize vascular smooth muscle cells from rat mesenteric arteries. The HNO donor Angeli's salt (0.1 nM-10 microM) caused a concentration-dependent hyperpolarization of vessels at resting tone and a simultaneous, concentration-dependent vasorelaxation and repolarization of vessels precontracted and depolarized with methoxamine. Both vasorelaxation and repolarization responses to Angeli's salt were significantly attenuated by both the HNO scavenger l-cysteine (3 mM) and the voltage-dependent K(+) (K(v)) channel inhibitor 4-aminopyridine (4-AP; 1 mM) and virtually abolished by the soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 microM) or 30 mM K(+). In contrast, NO(.) (0.01-1 microM) repolarized arteries to a lesser extent than HNO, and these responses were resistant to inhibition by ODQ (10 microM) and 4-AP (1 mM). Blockade of K(v) channels (1 mM 4-AP) also significantly inhibited the repolarization response to YC-1 (0.1-10 microM), confirming a role for sGC/cGMP in the activation of K(v) channels in this preparation. We conclude that HNO causes vasorelaxation via a cGMP-dependent activation of K(v) channels and that there are different profiles of vasorelaxant activity for the redox siblings HNO and NO(.).
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Affiliation(s)
- Joanne L Favaloro
- Discipline of Pharmaceutical Sciences, School of Medical Sciences, Royal Melbourne Institute of Technology, Univ., PO Box 71, Bundoora West, Victoria 3083, Australia.
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Cardioprotection: a radical view Free radicals in pre and postconditioning. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 2009; 1787:781-93. [PMID: 19248760 DOI: 10.1016/j.bbabio.2009.02.008] [Citation(s) in RCA: 158] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2008] [Revised: 02/12/2009] [Accepted: 02/13/2009] [Indexed: 12/13/2022]
Abstract
A series of brief (a few minutes) ischemia/reperfusion cycles (ischemic preconditioning, IP) limits myocardial injury produced by a subsequent prolonged period of coronary artery occlusion and reperfusion. Postconditioning (PostC), which is a series of brief (a few seconds) reperfusion/ischemia cycles at reperfusion onset, attenuates also ischemia/reperfusion injury. In recent years the main idea has been that reactive oxygen species (ROS) play an essential, though double-edged, role in cardioprotection: they may participate in reperfusion injury or may play a role as signaling elements of protection in the pre-ischemic phase. It has been demonstrated that preconditioning triggering is redox-sensitive, using either ROS scavengers or ROS generators. We have shown that nitroxyl triggers preconditioning via pro-oxidative, and/or nitrosative stress-related mechanism(s). Several metabolites, including acetylcholine, bradykinin, opioids and phenylephrine, trigger preconditioning-like protection via a mitochondrial K(ATP)-ROS-dependent mechanism. Intriguingly, and contradictory to the above mentioned theory of ROS as an obligatory part of reperfusion-induced damage, some studies suggest the possibility that some ROS at low concentrations could protect ischemic hearts against reperfusion injury. Yet, we demonstrated that ischemic PostC is also a cardioprotective phenomenon that requires the intervention of redox signaling to be protective. Emerging evidence suggests that in a preconditioning scenario a redox signal is required during the first few minutes of myocardial reperfusion following the index ischemic period. Intriguingly, the ROS signaling in the early reperfusion appear crucial to both preconditioning- and postconditioning-induced protection. Therefore, our and others' results suggest that the role of ROS in reperfusion may be reconsidered as they are not only deleterious.
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Mozaffarieh M, Grieshaber M, Orgül S, Flammer J. The Potential Value of Natural Antioxidative Treatment in Glaucoma. Surv Ophthalmol 2008; 53:479-505. [DOI: 10.1016/j.survophthal.2008.06.006] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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van Wonderen JH, Burlat B, Richardson DJ, Cheesman MR, Butt JN. The Nitric Oxide Reductase Activity of Cytochrome c Nitrite Reductase from Escherichia coli. J Biol Chem 2008; 283:9587-94. [DOI: 10.1074/jbc.m709090200] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
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Nitric oxide irreversibly inhibits cytochrome oxidase at low oxygen concentrations: Evidence for inverse oxygen concentration-dependent peroxynitrite formation. IUBMB Life 2007; 60:64-7. [DOI: 10.1002/iub.12] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Tavazzi B, Vagnozzi R, Signoretti S, Amorini AM, Belli A, Cimatti M, Delfini R, Di Pietro V, Finocchiaro A, Lazzarino G. Temporal window of metabolic brain vulnerability to concussions: oxidative and nitrosative stresses--part II. Neurosurgery 2007; 61:390-5; discussion 395-6. [PMID: 17806141 DOI: 10.1227/01.neu.0000255525.34956.3f] [Citation(s) in RCA: 114] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
OBJECTIVE In the present study, we investigated the occurrence of oxidative and nitrosative stresses in rats undergoing repeat mild traumatic brain injury (mTBI) delivered with increasing time intervals. METHODS Rats were subjected to two diffuse mTBIs (450 g/1 m height), with the second mTBI delivered after 1 (n = 6), 2 (n = 6), 3 (n = 6), 4 (n = 6), or 5 days (n = 6). The rats were sacrificed 48 hours after the last mTBI. Sham-operated animals were used as controls (n = 6). Concentrations of biochemical indices of oxidative stress (malondialdehyde, ascorbic acid, reduced and oxidized glutathione) and nitrosative stress (nitrite, nitrate) were synchronously measured by high-performance liquid chromatography in deproteinized tissue extracts (three right + three left hemispheres for each group of animals). RESULTS Increase of malondialdehyde, reduced/oxidized glutathione ratio, nitrite, nitrate, and decrease of ascorbic acid and glutathione were dependent on the interval between impacts with maximal changes recorded when mTBIs were spaced by 3 days. Biochemical markers of oxidative and nitrosative stresses were near control levels only in animals receiving mTBIs 5 days apart. CONCLUSION This study shows the remarkable negative contribution of reactive oxygen species overproduction and activation of inducible nitric oxide synthase in repeat mTBI. Because these effects were maximal when mTBIs were spaced by 3 days, it can be inferred that occurrence of a second mTBI within the temporal window of brain vulnerability not only causes profound derangement of mitochondrial functions, but also induces sustained oxidative and nitrosative stresses. Both phenomena certainly play a major role in the overall brain tissue damage occurring under these pathological conditions.
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Affiliation(s)
- Barbara Tavazzi
- Institute of Biochemistry and Clinical Biochemistry, Catholic University of Rome, Rome, Italy
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Moroz LL, Kohn AB. On the comparative biology of Nitric Oxide (NO) synthetic pathways: Parallel evolution of NO-mediated signaling. Nitric Oxide 2007. [DOI: 10.1016/s1872-2423(07)01001-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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