37 results on '"Donzelli, Sonia"'
Search Results
2. Nitroxyl as a Positive Inotropic Therapy in Heart Failure: cMyBP-C as a Target?: 92
- Author
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Goetz, Mara, Donzelli, Sonia, and Cuello, Friederike
- Published
- 2015
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3. Generation of nitroxyl by heme protein-mediated peroxidation of hydroxylamine but not N-hydroxy-L-arginine
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Donzelli, Sonia, Espey, Michael Graham, Flores-Santana, Wilmarie, Switzer, Christopher H., Yeh, Grace C., Huang, Jinming, Stuehr, Dennis J., King, S. Bruce, Miranda, Katrina M., and Wink, David A.
- Published
- 2008
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4. The chemical biology of nitric oxide: Implications in cellular signaling
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Thomas, Douglas D., Ridnour, Lisa A., Isenberg, Jeffrey S., Flores-Santana, Wilmarie, Switzer, Christopher H., Donzelli, Sonia, Hussain, Perwez, Vecoli, Cecilia, Paolocci, Nazareno, Ambs, Stefan, Colton, Carol A., Harris, Curtis C., Roberts, David D., and Wink, David A.
- Published
- 2008
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5. Comparing the chemical biology of NO and HNO
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Flores-Santana, Wilmarie, Switzer, Christopher, Ridnour, Lisa A., Basudhar, Debashree, Mancardi, Daniele, Donzelli, Sonia, Thomas, Douglas D., Miranda, Katrina M., Fukuto, Jon M., and Wink, David A.
- Published
- 2009
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6. Peroxynitrite and myocardial contractility: In vivo versus in vitro effects
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Katori, Tatsuo, Donzelli, Sonia, Tocchetti, Carlo G., Miranda, Katrina M., Cormaci, Gianfrancesco, Thomas, Douglas D., Ketner, Elizabeth A., Lee, Myung Jae, Mancardi, Daniele, Wink, David A., Kass, David A., and Paolocci, Nazareno
- Published
- 2006
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7. Discriminating formation of HNO from other reactive nitrogen oxide species
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Donzelli, Sonia, Espey, Michael Graham, Thomas, Douglas D., Mancardi, Daniele, Tocchetti, Carlo G., Ridnour, Lisa A., Paolocci, Nazareno, King, S. Bruce, Miranda, Katrina M., Lazzarino, Giuseppe, Fukuto, Jon M., and Wink, David A.
- Published
- 2006
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8. Nitroxyl exacerbates ischemic cerebral injury and oxidative neurotoxicity
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Choe, Chi-un, Lewerenz, Jan, Fischer, Gerry, Uliasz, Tracy F., Espey, Michael Graham, Hummel, Friedhelm C., King, Stephen Bruce, Schwedhelm, Edzard, Böger, Rainer H., Gerloff, Christian, Hewett, Sandra J., Magnus, Tim, and Donzelli, Sonia
- Published
- 2009
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9. Simultaneous high performance liquid chromatographic separation of purines, pyrimidines, N-acetylated amino acids, and dicarboxylic acids for the chemical diagnosis of inborn errors of metabolism
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Tavazzi, Barbara, Lazzarino, Giuseppe, Leone, Paola, Amorini, Angela Maria, Bellia, Francesco, Janson, Christopher G., Di Pietro, Valentina, Ceccarelli, Lia, Donzelli, Sonia, Francis, Jeremy S., and Giardina, Bruno
- Published
- 2005
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10. Nitroxyl Formation from NH2OH and NOHA Oxidation: 4
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Donzelli, Sonia, Switzer, Christopher H, Espey, Michael G, Thomas, Douglas D, Ridnour, Lisa a, Miranda, Katrina M, Tocchetti, Carlo G, Lazzarino, Giuseppe, Paolocci, Nazareno, and Wink, David a
- Published
- 2006
11. NITROXYL FORMATION FROM HYDROXYLAMINE BY MYOGLOBIN AND HYDROGEN PEROXIDE: 269
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Donzelli, Sonia, Espey, Michael G., Thomas, Douglas D., Mancardi, Daniele, Ridnour, Lisa A., Paolocci, Nazareno, Miranda, Katrina M., Lazzarino, Giuseppe, and Wink, David A.
- Published
- 2005
12. Hypothesis of the Postconcussive Vulnerable Brain: Experimental Evidence of Its Metabolic Occurrence
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Vagnozzi, Roberto, Signoretti, Stefano, Tavazzi, Barbara, Cimatti, Marco, Amorini, Angela Maria, Donzelli, Sonia, Delfini, Roberto, and Lazzarino, Giuseppe
- Published
- 2005
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13. IDENTIFICATION OF A NOVEL ADDUCT FROM HNO/NO- AND GLUTATHIONE REACTION: 266
- Author
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Donzelli, Sonia, Ridnour, Lisa, Mancardi, Daniele, Thomas, Douglas, Espey, Mike, Miranda, Katrina, and Wink, David
- Published
- 2004
14. THE NITROXYL DONORS ANGELIʼS SALT AND IPA/NO AFFORD EQUAL CARDIAC EARLY PRECONDITIONING-LIKE EFFECT THAT IS INDEPENDENT OF MITOCHONDRIAL KATP CHANNEL ACTIVATION.: 238
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Mancardi, Daniele, Ridnour, Lisa, Donzelli, Sonia, Miranda, Katrina M., Thomas, Douglas, Katori, Tatsuo, Espey, Mike, Paolocci, Nazareno, and Wink, David
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- 2004
15. Single-sample preparation for simultaneous cellular redox and energy state determination
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Lazzarino, Giuseppe, Amorini, Angela Maria, Fazzina, Giovanna, Vagnozzi, Roberto, Signoretti, Stefano, Donzelli, Sonia, Stasio, Enrico Di, Giardina, Bruno, and Tavazzi, Barbara
- Published
- 2003
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16. A simple, versatile and robust centrifugation‐based filtration protocol for the isolation and quantification of α‐synuclein monomers, oligomers and fibrils: Towards improving experimental reproducibility in α‐synuclein research
- Author
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Kumar, Senthil T., Donzelli, Sonia, Chiki, Anass, Syed, Muhammed Muazzam Kamil, and Lashuel, Hilal A.
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REPRODUCIBLE research , *LEWY body dementia , *MONOMERS , *MULTIPLE system atrophy , *PARKINSON'S disease , *AMYLOID beta-protein , *CENTRIFUGATION , *CELL separation - Abstract
Increasing evidence suggests that the process of alpha‐synuclein (α‐syn) aggregation from monomers into amyloid fibrils and Lewy bodies, via oligomeric intermediates plays an essential role in the pathogenesis of different synucleinopathies, including Parkinson's disease (PD), multiple system atrophy and dementia with Lewy bodies (DLB). However, the nature of the toxic species and the mechanisms by which they contribute to neurotoxicity and disease progression remain elusive. Over the past two decades, significant efforts and resources have been invested in studies aimed at identifying and targeting toxic species along the pathway of α‐syn fibrillization. Although this approach has helped to advance the field and provide insights into the biological properties and toxicity of different α‐syn species, many of the fundamental questions regarding the role of α‐syn aggregation in PD remain unanswered, and no therapeutic compounds targeting α‐syn aggregates have passed clinical trials. Several factors have contributed to this slow progress, including the complexity of the aggregation pathways and the heterogeneity and dynamic nature of α‐syn aggregates. In the majority of experiment, the α‐syn samples used contain mixtures of α‐syn species that exist in equilibrium and their ratio changes upon modifying experimental conditions. The failure to quantitatively account for the distribution of different α‐syn species in different studies has contributed not only to experimental irreproducibility but also to misinterpretation of results and misdirection of valuable resources. Towards addressing these challenges and improving experimental reproducibility in Parkinson's research, we describe here a simple centrifugation‐based filtration protocol for the isolation, quantification and assessment of the distribution of α‐syn monomers, oligomers and fibrils, in heterogeneous α‐syn samples of increasing complexity. The protocol is simple, does not require any special instrumentation and can be performed rapidly on multiple samples using small volumes. Here, we present and discuss several examples that illustrate the applications of this protocol and how it could contribute to improving the reproducibility of experiments aimed at elucidating the structural basis of α‐syn aggregation, seeding activity, toxicity and pathology spreading. This protocol is applicable, with slight modifications, to other amyloid‐forming proteins. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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17. Dual mechanisms of HNO generation by a nitroxyl prodrug of the diazeniumdiolate (NONOate) class
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Andrei, Daniela, Salmon, Debra J., Donzelli, Sonia, Wahab, Azadeh, Klose, John R., Citro, Michael L., Saavedra, Joseph E., Wink, David A., Miranda, Katrina M., and Keefer, Larry K.
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Diazo compounds -- Structure ,Diazo compounds -- Chemical properties ,Heart failure -- Prevention ,Hydrolysis -- Analysis ,Nitrogen oxide -- Chemical properties ,Prodrugs -- Chemical properties ,Prodrugs -- Research ,Chemistry - Abstract
A novel caged form of the highly reactive bioeffector molecule, nitroxyl (HNO) is described. Micromolar concentrations of prodrug iPrHN-N(O)[double bond]NO-C[H.sub.2]OAc (AcOM-IPA/NO) has exhibited more potent sarcomere shortening efforts relative to IPA/NO on ventricular myocytes isolated from wild-type mouse hearts, which has shown that AcOM-IPA/NO is a promising lead compound for the development of heart failure therapies.
- Published
- 2010
18. S-glutathiolation impairs phosphoregulation and function of cardiac myosin-binding protein C in human heart failure.
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Stathopoulou, Konstantina, Wittig, Ilka, Heidler, Juliana, Piasecki, Angelika, Richter, Florian, Diering, Simon, der Velden, Jolanda van, Buck, Friedrich, Donzelli, Sonia, Schröder, Ewald, Wijnker, Paul J. M., Voigt, Niels, Dobrev, Dobromir, Sadayappan, Sakthivel, Eschenhagen, Thomas, Carrier, Lucie, Eaton, Philip, and Cuello, Friederike
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HEART failure patients ,CARDIAC contraction ,MYOSIN ,HEART physiology ,CARRIER proteins ,PROTEIN kinases - Abstract
Cardiac myosin-binding protein C (cMyBP-C) regulates actin-myosin interaction and thereby cardiac myocyte contraction and relaxation. This physiologic function is regulated by cMyBP-C phosphorylation. In our study, reduced site-specific cMyBP-C phosphorylation coincided with increased S-glutathiolation in ventricular tissue from patients with dilated or ischemic cardiomyopathy compared to nonfailing donors. We used redox proteomics, to identify constitutive and disease-specific S-glutathiolation sites in cMyBP-C in donor and patient samples, respectively. Among those, a cysteine cluster in the vicinity of the regulatory phosphorylation sites within the myosin S2 interaction domain C1-M-C2 was identified and showed enhanced S-glutathiolation in patients. In vitro S-glutathiolation of recombinant cMyBP-C C1-M-C2 occurred predominantly at Cys249, which attenuated phosphorylation by protein kinases. Exposure to glutathione disulfide induced cMyBP-C S-glutathiolation, which functionally decelerated the kinetics of Ca
2+ -activated force development in ventricular myocytes from wild-type, but not those from Mybpc3-targeted knockout mice. These oxidation events abrogate protein kinase-mediated phosphorylation of cMyBP-C and therefore potentially contribute to the reduction of its phosphorylation and the contractile dysfunction observed in human heart failure. [ABSTRACT FROM AUTHOR]- Published
- 2016
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19. Impact of AT2 Receptor Deficiency on Postnatal Cardiovascular Development.
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Biermann, Daniel, Heilmann, Andreas, Didié, Michael, Schlossarek, Saskia, Wahab, Azadeh, Grimm, Michael, Römer, Maria, Reichenspurner, Hermann, Sultan, Karim R., Steenpass, Anna, Ergün, Süleyman, Donzelli, Sonia, Carrier, Lucie, Ehmke, Heimo, Zimmermann, Wolfram H., Hein, Lutz, Böger, Rainer H., and Benndorf, Ralf A.
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ANGIOTENSIN receptors ,ANGIOTENSIN II ,CARDIOVASCULAR system ,GENE expression ,LABORATORY mice ,ISOPROTERENOL - Abstract
Background: The angiotensin II receptor subtype 2 (AT2 receptor) is ubiquitously and highly expressed in early postnatal life. However, its role in postnatal cardiac development remained unclear. Methodology/Principal Findings: Hearts from 1, 7, 14 and 56 days old wild-type (WT) and AT2 receptor-deficient (KO) mice were extracted for histomorphometrical analysis as well as analysis of cardiac signaling and gene expression. Furthermore, heart and body weights of examined animals were recorded and echocardiographic analysis of cardiac function as well as telemetric blood pressure measurements were performed. Moreover, gene expression, sarcomere shortening and calcium transients were examined in ventricular cardiomyocytes isolated from both genotypes. KO mice exhibited an accelerated body weight gain and a reduced heart to body weight ratio as compared to WT mice in the postnatal period. However, in adult KO mice the heart to body weight ratio was significantly increased most likely due to elevated systemic blood pressure. At postnatal day 7 ventricular capillarization index and the density of α-smooth muscle cell actin-positive blood vessels were higher in KO mice as compared to WT mice but normalized during adolescence. Echocardiographic assessment of cardiac systolic function at postnatal day 7 revealed decreased contractility of KO hearts in response to beta-adrenergic stimulation. Moreover, cardiomyocytes from KO mice showed a decreased sarcomere shortening and an increased peak Ca
2+ transient in response to isoprenaline when stimulated concomitantly with angiotensin II. Conclusion: The AT2 receptor affects postnatal cardiac growth possibly via reducing body weight gain and systemic blood pressure. Moreover, it moderately attenuates postnatal vascularization of the heart and modulates the beta adrenergic response of the neonatal heart. These AT2 receptor-mediated effects may be implicated in the physiological maturation process of the heart. [ABSTRACT FROM AUTHOR]- Published
- 2012
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20. Nitroxyl exacerbates ischemic cerebral injury and oxidative neurotoxicity.
- Author
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Chi-un Choe, Lewerenz, Jan, Fischer, Gerry, Uliasz, Tracy F., Espey, Michael Graham, Hummel, Friedhelm C., King, Stephen Bruce, Schwedhelm, Edzard, Böger, Rainer H., Gerloff, Christian, Hewett, Sandra J., Magnus, Tim, and Donzelli, Sonia
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NEUROTOXICOLOGY ,CARDIAC contraction ,ISCHEMIA ,REPERFUSION injury ,CARDIOVASCULAR system - Abstract
Nitroxyl (HNO) donor compounds function as potent vasorelaxants, improve myocardial contractility and reduce ischemia-reperfusion injury in the cardiovascular system. With respect to the nervous system, HNO donors have been shown to attenuate NMDA receptor activity and neuronal injury, suggesting that its production may be protective against cerebral ischemic damage. Hence, we studied the effect of the classical HNO-donor, Angeli’s salt (AS), on a cerebral ischemia/reperfusion injury in a mouse model of experimental stroke and on related in vitro paradigms of neurotoxicity. I.p. injection of AS (40 μmol/kg) in mice prior to middle cerebral artery occlusion exacerbated cortical infarct size and worsened the persistent neurological deficit. AS not only decreased systolic blood pressure, but also induced systemic oxidative stress in vivo indicated by increased isoprostane levels in urine and serum. In vitro, neuronal damage induced by oxygen-glucose-deprivation of mature neuronal cultures was exacerbated by AS, although there was no direct effect on glutamate excitotoxicity. Finally, AS exacerbated oxidative glutamate toxicity – that is, cell death propagated via oxidative stress in immature neurons devoid of ionotropic glutamate receptors. Taken together, our data indicate that HNO might worsen cerebral ischemia-reperfusion injury by increasing oxidative stress and decreasing brain perfusion at concentrations shown to be cardioprotective in vivo. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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21. 870-3 Metalloproteinase inhibition prevents diastolic stiffening, AMP-breakdown, and oxypurine accumulation in accelerated heart failure
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Paolocci, Nazareno, Tavazzi, Barbara, Biondi, Roberto, Gluzband, Yehezkiel A, Amorini, Mariangela, Tocchetti, Carlo G, Donzelli, Sonia, Crow, Michael T, Lazzarino, Giuseppe, and Kass, David A
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- 2004
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22. 92 - Nitroxyl as a Positive Inotropic Therapy in Heart Failure: cMyBP-C as a Target?
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Goetz, Mara, Donzelli, Sonia, and Cuello, Friederike
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NITROXYL , *CARDIOTONIC agents , *HEART failure treatment , *MYOSIN , *CARRIER proteins - Published
- 2015
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23. P044. Nitroxyl formation from NH2OH and NOHA oxidation
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Donzelli, Sonia, Switzer, Christopher H., Espey, Michael G., Thomas, Douglas D., Ridnour, Lisa A., Miranda, Katrina M., Tocchetti, Carlo G., Lazzarino, Giuseppe, Paolocci, Nazareno, and Wink, David A.
- Published
- 2006
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24. Receptor-independent modulation of cAMP-dependent protein kinase and protein phosphatase signaling in cardiac myocytes by oxidizing agents.
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Diering, Simon, Stathopoulou, Konstantina, Goetz, Mara, Rathjens, Laura, Harder, Sönke, Piasecki, Angelika, Raabe, Janice, Schulz, Steven, Brandt, Mona, Pflaumenbaum, Julia, Fuchs, Ulrike, Donzelli, Sonia, Sadayappan, Sakthivel, Nikolaev, Viacheslav O., Flenner, Frederik, Ehler, Elisabeth, and Cuello, Friederike
- Subjects
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PHOSPHOPROTEIN phosphatases , *PROTEIN kinases , *OXIDIZING agents , *CARDIAC contraction , *CYCLIC-AMP-dependent protein kinase - Abstract
The contraction and relaxation of the heart is controlled by stimulation of the b1-adrenoreceptor (AR) signaling cascade, which leads to activation of cAMP-dependent protein kinase (PKA) and subsequent cardiac protein phosphorylation. Phosphorylation is counteracted by the main cardiac protein phosphatases, PP2A and PP1. Both kinase and phosphatases are sensitive to intramolecular disulfide formation in their catalytic subunits that inhibits their activity. Additionally, intermolecular disulfide formation between PKA type I regulatory subunits (PKA-RI) has been described to enhance PKA's affinity for protein kinase A anchoring proteins, which alters its subcellular distribution. Nitroxyl donors have been shown to affect contractility and relaxation, but the mechanistic basis for this effect is unclear. The present study investigates the impact of several nitroxyl donors and the thiol-oxidizing agent diamide on cardiac myocyte protein phosphorylation and oxidation. Although all tested compounds equally induced intermolecular disulfide formation in PKA-RI, only 1-nitrosocyclohexalycetate (NCA) and diamide induced reproducible protein phosphorylation. Phosphorylation occurred independently of b1-AR activation, but was abolished after pharmacological PKA inhibition and thus potentially attributable to increased PKA activity. NCA treatment of cardiac myocytes induced translocation of PKA and phosphatases to the myofilament compartment as shown by fractionation, immunofluorescence, and proximity ligation assays. Assessment of kinase and phosphatase activity within the myofilament fraction of cardiac myocytes after exposure to NCA revealed activation of PKA and inhibition of phosphatase activity thus explaining the increase in phosphorylation. The data suggest that the NCA-mediated effect on cardiac myocyte protein phosphorylation orchestrates alterations in the kinase/phosphatase balance. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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25. Enzymatic generation of the NO/HNO-releasing IPA/NO anion at controlled rates in physiological media using β-galactosidase.
- Author
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Holland, Ryan J., Paulisch, Rika, Cao, Zhao, Keefer, Larry K., Saavedra, Joseph E., and Donzelli, Sonia
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ENZYMATIC analysis , *NITRIC oxide , *GALACTOSIDASES , *HYDROLYSIS , *ANIONS , *SODIUM , *DIAZENES - Abstract
Highlights: [•] We introduce a novel prodrug form of the HNO/NO-releasing IPA/NO anion. [•] Its hydrolysis by galactosidase is directly proportional to enzyme concentration. [•] Thus the rate of HNO/NO generation can be precisely programmed. [•] This enzyme/substrate combination displayed positive inotropism in myocyte culture. [Copyright &y& Elsevier]
- Published
- 2013
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26. The new HNO donor, 1-nitrosocyclohexyl acetate, increases contractile force in normal and β-adrenergically desensitized ventricular myocytes
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El-Armouche, Ali, Wahab, Azadeh, Wittköpper, Katrin, Schulze, Thomas, Böttcher, Felix, Pohlmann, Lutz, King, S. Bruce, DuMond, Jenna F., Gerloff, Christian, Böger, Rainer H., Eschenhagen, Thomas, Carrier, Lucie, and Donzelli, Sonia
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CONTRACTILE vacuole , *ADRENERGIC receptors , *HEART failure , *SARCOPLASMIC reticulum , *CYTOPLASMIC filaments , *HEART cells , *LABORATORY mice - Abstract
Abstract: Contractile dysfunction and diminished response to β-adrenergic agonists are characteristics for failing hearts. Chemically donated nitroxyl (HNO) improves contractility in failing hearts and thus may have therapeutic potential. Yet, there is a need for pharmacologically suitable donors. In this study we tested whether the pure and long acting HNO donor, 1-nitrosocyclohexyl acetate (NCA), affects contractile force in normal and pathological ventricular myocytes (VMs) as well as in isolated hearts. VMs were isolated from mice either subjected to isoprenaline-infusion (ISO; 30μg/g per day) or to vehicle (0.9% NaCl) for 5days. Sarcomere shortening and Ca2+ transients were simultaneously measured using the IonOptix system. Force of contraction of isolated hearts was measured by a Langendorff-perfusion system. NCA increased peak sarcomere shortening by+40–200% in a concentration-dependent manner (EC50 ∼55μM). Efficacy and potency did not differ between normal and chronic ISO VMs, despite the fact that the latter displayed a markedly diminished inotropic response to acute β-adrenergic stimulation with ISO (1μM). NCA (60μM) increased peak sarcomere shortening and Ca2+ transient amplitude by ∼200% and ∼120%, respectively, suggesting effects on both myofilament Ca2+ sensitivity and sarcoplasmic reticulum (SR) Ca2+ cycling. Importantly, NCA did not affect diastolic Ca2+ or SR Ca2+ content, as assessed by rapid caffeine application. NCA (45μM) increased force of contraction by 30% in isolated hearts. In conclusion, NCA increased contractile force in normal and β-adrenergically desensitized VMs as well as in isolated mouse hearts. This profile warrants further investigations of this HNO donor in the context of heart failure. [Copyright &y& Elsevier]
- Published
- 2010
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27. The emergence of nitroxyl (HNO) as a pharmacological agent
- Author
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Switzer, Christopher H., Flores-Santana, Wilmarie, Mancardi, Daniele, Donzelli, Sonia, Basudhar, Debashree, Ridnour, Lisa A., Miranda, Katrina M., Fukuto, Jon M., Paolocci, Nazareno, and Wink, David A.
- Subjects
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ISCHEMIA , *NITROGEN oxides , *BIOCHEMICAL research , *REPERFUSION injury , *RYANODINE , *CARDIOTONIC agents , *CALCIUM channels , *HEART failure - Abstract
Abstract: Once a virtually unknown nitrogen oxide, nitroxyl (HNO) has emerged as a potential pharmacological agent. Recent advances in the understanding of the chemistry of HNO has led to the an understanding of HNO biochemistry which is vastly different from the known chemistry and biochemistry of nitric oxide (NO), the one-electron oxidation product of HNO. The cardiovascular roles of NO have been extensively studied, as NO is a key modulator of vascular tone and is involved in a number of vascular related pathologies. HNO displays unique cardiovascular properties and has been shown to have positive lusitropic and ionotropic effects in failing hearts without a chronotropic effect. Additionally, HNO causes a release of CGRP and modulates calcium channels such as ryanodine receptors. HNO has shown beneficial effects in ischemia reperfusion injury, as HNO treatment before ischemia-reperfusion reduces infarct size. In addition to the cardiovascular effects observed, HNO has shown initial promise in the realm of cancer therapy. HNO has been demonstrated to inhibit GAPDH, a key glycolytic enzyme. Due to the Warburg effect, inhibiting glycolysis is an attractive target for inhibiting tumor proliferation. Indeed, HNO has recently been shown to inhibit tumor proliferation in mouse xenografts. Additionally, HNO inhibits tumor angiogenesis and induces cancer cell apoptosis. The effects seen with HNO donors are quite different from NO donors and in some cases are opposite. The chemical nature of HNO explains how HNO and NO, although closely chemically related, act so differently in biochemical systems. This also gives insight into the potential molecular motifs that may be reactive towards HNO and opens up a novel field of pharmacological development. [Copyright &y& Elsevier]
- Published
- 2009
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28. Superoxide Fluxes Limit Nitric Oxide-induced Signaling.
- Author
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Thomas, Douglas D., Ridnour, Lisa A., Espey, Michael Graham, Donzelli, Sonia, Ambs, Stefan, Hussain, S. Perwez, Harris, Curtis C., DeGraff, William, Roberts, David D., Mitchell, James B., and Wink, David A.
- Subjects
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SUPEROXIDES , *NITRIC oxide , *NITROGEN compounds , *MICROBIAL genetics , *RADICALS (Chemistry) , *BIOCHEMISTRY - Abstract
Independently, superoxide (O2-) and nitric oxide (NO) are biologically important signaling molecules. When co-generated, these radicals react rapidly to form powerful oxidizing and nitrating intermediates. Although this reaction was once thought to be solely cytotoxic, herein we demonstrate using MCF7, macrophage, and endothelial cells that when nanomolar levels of NO and O2- were produced concomitantly, the effective NO concentration was established by the relative fluxes of these two radicals. Differential regulation of sGC, pERK, HIF-1α, and p53 were used as biological dosimeters for NO concentration. Introduction of intracellular- or extracellular-generated O2- during NO generation resulted in a concomitant increase in oxidative intermediates with a decrease in steady-state NO concentrations and a proportional reduction in the levels of sGC, ERK, HIF-1α, and p53 regulation. NO responses were restored by addition of SOD. The intermediates formed from the reactions of NO with O2- were non-toxic, did not form 3-nitrotyrosine, nor did they elicit any signal transduction responses. H2O2 in bolus or generated from the dismutation of O2- by SOD, was cytotoxic at high concentrations and activated p53 independent of NO. This effect was completely inhibited by catalase, suppressed by NO, and exacerbated by intracellular catalase inhibition. We conclude that the reaction of O2- with NO is an important regulatory mechanism, which modulates signaling pathways by limiting steady-state levels of NO and preventing H2O2 formation from O2-. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
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29. A NAC domain mutation (E83Q) unlocks the pathogenicity of human alpha-synuclein and recapitulates its pathological diversity.
- Author
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Kumar ST, Mahul-Mellier AL, Hegde RN, Rivière G, Moons R, Ibáñez de Opakua A, Magalhães P, Rostami I, Donzelli S, Sobott F, Zweckstetter M, and Lashuel HA
- Subjects
- Humans, Lewy Bodies chemistry, Lewy Bodies metabolism, Lewy Bodies pathology, Mutation, Virulence, Parkinson Disease metabolism, alpha-Synuclein genetics
- Abstract
The alpha-synuclein mutation E83Q, the first in the NAC domain of the protein, was recently identified in a patient with dementia with Lewy bodies. We investigated the effects of this mutation on the aggregation of aSyn monomers and the structure, morphology, dynamic, and seeding activity of the aSyn fibrils in neurons. We found that it markedly accelerates aSyn fibrillization and results in the formation of fibrils with distinct structural and dynamic properties. In cells, this mutation is associated with higher levels of aSyn, accumulation of pS129, and increased toxicity. In a neuronal seeding model of Lewy body (LB) formation, the E83Q mutation significantly enhances the internalization of fibrils into neurons, induces higher seeding activity, and results in the formation of diverse aSyn pathologies, including the formation of LB-like inclusions that recapitulate the immunohistochemical and morphological features of brainstem LBs observed in brains of patients with Parkinson's disease.
- Published
- 2022
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30. Oxidant sensor in the cGMP-binding pocket of PKGIα regulates nitroxyl-mediated kinase activity.
- Author
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Donzelli S, Goetz M, Schmidt K, Wolters M, Stathopoulou K, Diering S, Prysyazhna O, Polat V, Scotcher J, Dees C, Subramanian H, Butt E, Kamynina A, Schobesberger S, King SB, Nikolaev VO, de Wit C, Leichert LI, Feil R, Eaton P, and Cuello F
- Subjects
- Animals, Catalytic Domain, Cells, Cultured, Cyclic GMP-Dependent Protein Kinase Type I genetics, Cysteine genetics, Fluorescence Resonance Energy Transfer, HEK293 Cells, Humans, Male, Mass Spectrometry, Mice, Muscle, Smooth, Vascular cytology, Muscle, Smooth, Vascular metabolism, Oxidation-Reduction, Cyclic GMP metabolism, Cyclic GMP-Dependent Protein Kinase Type I chemistry, Cyclic GMP-Dependent Protein Kinase Type I metabolism, Disulfides metabolism, Mutagenesis, Site-Directed, Nitrogen Oxides pharmacology
- Abstract
Despite the mechanisms for endogenous nitroxyl (HNO) production and action being incompletely understood, pharmacological donors show broad therapeutic promise and are in clinical trials. Mass spectrometry and site-directed mutagenesis showed that chemically distinct HNO donors 1-nitrosocyclohexyl acetate or Angeli's salt induced disulfides within cGMP-dependent protein kinase I-alpha (PKGIα), an interdisulfide between Cys42 of the two identical subunits of the kinase and a previously unobserved intradisulfide between Cys117 and Cys195 in the high affinity cGMP-binding site. Kinase activity was monitored in cells transfected with wildtype (WT), Cys42Ser or Cys117/195Ser PKGIα that cannot form the inter- or intradisulfide, respectively. HNO enhanced WT kinase activity, an effect significantly attenuated in inter- or intradisulfide-deficient PKGIα. To investigate whether the intradisulfide modulates cGMP binding, real-time imaging was performed in vascular smooth muscle cells expressing a FRET-biosensor comprising the cGMP-binding sites of PKGIα. HNO induced FRET changes similar to those elicited by an increase of cGMP, suggesting that intradisulfide formation is associated with activation of PKGIα. Intradisulfide formation in PKGIα correlated with enhanced HNO-mediated vasorelaxation in mesenteric arteries in vitro and arteriolar dilation in vivo in mice. HNO induces intradisulfide formation in PKGIα, inducing the same effect as cGMP binding, namely kinase activation and thus vasorelaxation.
- Published
- 2017
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31. Pharmacological characterization of 1-nitrosocyclohexyl acetate, a long-acting nitroxyl donor that shows vasorelaxant and antiaggregatory effects.
- Author
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Donzelli S, Fischer G, King BS, Niemann C, DuMond JF, Heeren J, Wieboldt H, Baldus S, Gerloff C, Eschenhagen T, Carrier L, Böger RH, and Espey MG
- Subjects
- Acetates pharmacokinetics, Animals, Aorta, Thoracic drug effects, Aorta, Thoracic metabolism, Apolipoproteins E deficiency, Atherosclerosis metabolism, Atherosclerosis physiopathology, Atherosclerosis prevention & control, Blood Platelets cytology, Blood Platelets drug effects, Disease Models, Animal, Dose-Response Relationship, Drug, Endothelium, Vascular drug effects, Endothelium, Vascular metabolism, Endothelium, Vascular physiology, Half-Life, Humans, In Vitro Techniques, Mice, Mice, Inbred C57BL, Nitric Oxide Donors pharmacokinetics, Nitroso Compounds pharmacokinetics, Platelet Aggregation drug effects, Platelet Aggregation Inhibitors pharmacokinetics, Vasodilator Agents pharmacokinetics, Acetates pharmacology, Nitric Oxide Donors pharmacology, Nitrogen Oxides metabolism, Nitroso Compounds pharmacology, Platelet Aggregation Inhibitors pharmacology, Vasodilation drug effects, Vasodilator Agents pharmacology
- Abstract
Nitroxyl (HNO) donors have potential benefit in the treatment of heart failure and other cardiovascular diseases. 1-Nitrosocyclohexyl acetate (NCA), a new HNO donor, in contrast to the classic HNO donors Angeli's salt and isopropylamine NONOate, predominantly releases HNO and has a longer half-life. This study investigated the vasodilatative properties of NCA in isolated aortic rings and human platelets and its mechanism of action. NCA was applied on aortic rings isolated from wild-type mice and apolipoprotein E-deficient mice and in endothelial-denuded aortae. The mechanism of action of HNO was examined by applying NCA in the absence and presence of the HNO scavenger glutathione (GSH) and inhibitors of soluble guanylyl cyclase (sGC), adenylyl cyclase (AC), calcitonin gene-related peptide receptor (CGRP), and K(+) channels. NCA induced a concentration-dependent relaxation (EC(50), 4.4 µM). This response did not differ between all groups, indicating an endothelium-independent relaxation effect. The concentration-response was markedly decreased in the presence of excess GSH; the nitric oxide scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide had no effect. Inhibitors of sGC, CGRP, and voltage-dependent K(+) channels each significantly impaired the vasodilator response to NCA. In contrast, inhibitors of AC, ATP-sensitive K(+) channels, or high-conductance Ca(2+)-activated K(+) channels did not change the effects of NCA. NCA significantly reduced contractile response and platelet aggregation mediated by the thromboxane A(2) mimetic 9,11-dideoxy-11α,9α-epoxymethanoprostaglandin F(2)(α) in a cGMP-dependent manner. In summary, NCA shows vasoprotective effects and may have a promising profile as a therapeutic agent in vascular dysfunction, warranting further evaluation.
- Published
- 2013
- Full Text
- View/download PDF
32. The specificity of nitroxyl chemistry is unique among nitrogen oxides in biological systems.
- Author
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Flores-Santana W, Salmon DJ, Donzelli S, Switzer CH, Basudhar D, Ridnour L, Cheng R, Glynn SA, Paolocci N, Fukuto JM, Miranda KM, and Wink DA
- Subjects
- Animals, Humans, Metalloproteins chemistry, Metalloproteins metabolism, Nitrogen Oxides chemistry, Sulfhydryl Compounds chemistry, Sulfhydryl Compounds metabolism, Nitrogen Oxides metabolism
- Abstract
The importance of nitric oxide in mammalian physiology has been known for nearly 30 years. Similar attention for other nitrogen oxides such as nitroxyl (HNO) has been more recent. While there has been speculation as to the biosynthesis of HNO, its pharmacological benefits have been demonstrated in several pathophysiological settings such as cardiovascular disorders, cancer, and alcoholism. The chemical biology of HNO has been identified as related to, but unique from, that of its redox congener nitric oxide. A summary of these findings as well as a discussion of possible endogenous sources of HNO is presented in this review.
- Published
- 2011
- Full Text
- View/download PDF
33. Playing with cardiac "redox switches": the "HNO way" to modulate cardiac function.
- Author
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Tocchetti CG, Stanley BA, Murray CI, Sivakumaran V, Donzelli S, Mancardi D, Pagliaro P, Gao WD, van Eyk J, Kass DA, Wink DA, and Paolocci N
- Subjects
- Animals, Humans, Models, Biological, Myocardium metabolism, Myocardium pathology, Nitric Oxide Synthase metabolism, Oxidation-Reduction, Reactive Oxygen Species metabolism, Reperfusion Injury metabolism, Sulfhydryl Compounds metabolism, Nitrogen Oxides metabolism
- Abstract
The nitric oxide (NO(•)) sibling, nitroxyl or nitrosyl hydride (HNO), is emerging as a molecule whose pharmacological properties include providing functional support to failing hearts. HNO also preconditions myocardial tissue, protecting it against ischemia-reperfusion injury while exerting vascular antiproliferative actions. In this review, HNO's peculiar cardiovascular assets are discussed in light of its unique chemistry that distinguish HNO from NO(•) as well as from reactive oxygen and nitrogen species such as the hydroxyl radical and peroxynitrite. Included here is a discussion of the possible routes of HNO formation in the myocardium and its chemical targets in the heart. HNO has been shown to have positive inotropic/lusitropic effects under normal and congestive heart failure conditions in animal models. The mechanistic intricacies of the beneficial cardiac effects of HNO are examined in cellular models. In contrast to β-receptor/cyclic adenosine monophosphate/protein kinase A-dependent enhancers of myocardial performance, HNO uses its "thiophylic" nature as a vehicle to interact with redox switches such as cysteines, which are located in key components of the cardiac electromechanical machinery ruling myocardial function. Here, we will briefly review new features of HNO's cardiovascular effects that when combined with its positive inotropic/lusitropic action may render HNO donors an attractive addition to the current therapeutic armamentarium for treating patients with acutely decompensated congestive heart failure.
- Published
- 2011
- Full Text
- View/download PDF
34. Nitroxyl in the central nervous system.
- Author
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Choe CU, Lewerenz J, Gerloff C, Magnus T, and Donzelli S
- Subjects
- Animals, Calcium metabolism, Central Nervous System drug effects, Humans, Nitric Oxide Synthase Type I metabolism, Nitrites pharmacology, Oxidative Stress physiology, Central Nervous System metabolism, Nitrogen Oxides metabolism
- Abstract
Nitroxyl (HNO) is the one-electron-reduced and protonated congener of nitric oxide (NO). Compared to NO, it is far more reactive with thiol groups either in proteins or in small antioxidant molecules either converting those into sulfinamides or inducing disulfide bond formation. HNO might mediate cytoprotective changes of protein function through thiol modifications. However, HNO is a strong oxidant that in vitro reacts with glutathione to form glutathione disulfide and glutathione sulfinamide. The resulting oxidative stress might aggravate tissue damage in inflammatory diseases. In this review, we will summarize the current knowledge of how exogenous HNO affects the central nervous system, especially nerve cells and glia in health and disease. Unlike most other organs, the brain is separated from the circulation by the blood-brain barrier, which limits access of many pharmacological compounds. Given that, we will review what is known about the ability of currently used HNO donors to cross the blood-brain barrier. Moreover, considering that the physiology and composition of the brain has unique properties, for example, expression of brain-specific enzymes like neuronal NO synthase, its high iron content, and increased energy metabolism, we will discuss possible sources of endogenous HNO in the brain.
- Published
- 2011
- Full Text
- View/download PDF
35. Asbestos redirects nitric oxide signaling through rapid catalytic conversion to nitrite.
- Author
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Thomas DD, Espey MG, Pociask DA, Ridnour LA, Donzelli S, and Wink DA
- Subjects
- Animals, Cattle, Humans, Hypoxia-Inducible Factor 1, alpha Subunit drug effects, Phosphoserine, Tumor Suppressor Protein p53 drug effects, Asbestos pharmacology, Nitric Oxide physiology, Nitrites metabolism, Serum Albumin, Bovine drug effects, Signal Transduction drug effects
- Abstract
Asbestos exposure is strongly associated with the development of malignant mesothelioma, yet the mechanistic basis of this observation has not been resolved. Carcinogenic transformation or tumor progression mediated by asbestos may be related to the generation of free radical species and perturbation of cell signaling and transcription factors. We report here that exposure of human mesothelioma or lung carcinoma cells to nitric oxide (NO) in the presence of crocidolite asbestos resulted in a marked decrease in intracellular nitrosation and diminished NO-induced posttranslational modifications of tumor-associated proteins (hypoxia-inducible factor-1alpha and p53). Crocidolite rapidly scavenged NO with concomitant conversion to nitrite (NO(2)(-)). Crocidolite also catalyzed the nitration of cellular proteins in the presence of NO(2)(-) and hydrogen peroxide. Nitrated protein adducts are a prominent feature of asbestos-induced lung injury. These data highlight the ability of asbestos to induce phenotypic cellular changes through two processes: (a) by directly reducing bioactive NO levels and preventing its subsequent interaction with target molecules and (b) by increasing oxidative damage and protein modifications through NO(2) production and 3-nitrotyrosine formation.
- Published
- 2006
- Full Text
- View/download PDF
36. The biphasic nature of nitric oxide responses in tumor biology.
- Author
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Ridnour LA, Thomas DD, Donzelli S, Espey MG, Roberts DD, Wink DA, and Isenberg JS
- Subjects
- Animals, Biomimetic Materials pharmacology, Dose-Response Relationship, Drug, Endothelium, Vascular drug effects, Humans, Models, Biological, Neoplasm Metastasis drug therapy, Neoplasms blood supply, Neovascularization, Pathologic drug therapy, Oxidation-Reduction, Thrombospondin 1 pharmacology, Time Factors, Biology, Neoplasms metabolism, Nitric Oxide pharmacology
- Abstract
The dual or biphasic responses of cancer to nitric oxide (NO) arise from its concentration dependent ability to regulate tumor growth, migration, invasion, survival, angiogenesis, and metastasis. The outcome of these various NO-dependent processes is dictated by several factors including NO flux, the chemical redox environment, and the duration of NO exposure. Further, it was recently discovered that an NO-induced redox flux in vascular endothelial cells hypersensitizes these cells to the antiangiogenic effects of thrombospondin-1. This suggests a novel treatment paradigm for targeting tumor-driven angiogenesis that combines redox modulation with mimetic derivatives of thrombospondin-1. This article discusses the biphasic nature of NO in cancer biology and the implications of NO-driven redox flux for modulation of tumor-stimulated angiogenesis, growth, and metastasis.
- Published
- 2006
- Full Text
- View/download PDF
37. The activation of metabolites of nitric oxide synthase by metals is both redox and oxygen dependent: a new feature of nitrogen oxide signaling.
- Author
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Donzelli S, Switzer CH, Thomas DD, Ridnour LA, Espey MG, Isenberg JS, Tocchetti CG, King SB, Lazzarino G, Miranda KM, Roberts DD, Feelisch M, and Wink DA
- Subjects
- Arginine metabolism, Forecasting, Hydroxylamines metabolism, Nitric Oxide Synthase Type I, Nitric Oxide Synthase Type II, Nitrites metabolism, Oxidation-Reduction, Metals pharmacology, Nitric Oxide metabolism, Nitric Oxide Synthase chemistry, Nitrogen Oxides chemistry, Oxygen chemistry, Signal Transduction
- Abstract
Nitrite (NO(2)-), N (G)-hydroxy-L-arginine (NOHA), and hydroxylamine (NH(2)OH) are products of nitric oxide synthase (NOS) activity and can also be formed by secondary reactions of nitric oxide (NO). These compounds are commonly considered to be rather stable and as such to be dosimeters of NO biosynthesis. However, each can be converted via metal-catalyzed reactions into either NO or other reactive nitrogen oxide species (RNOS), such as nitrogen dioxide (NO(2)) and nitroxyl (HNO), which have biologic activities distinct from those of the parent molecules. Consequently, certain aspects of tissue regulation controlled by RNOS may be dictated to a significant extent by metal-dependent reactions, thereby offering unique advantages for cellular and tissue regulation. For instance, because many metal-catalyzed reactions depend on the redox and oxygen status of the cellular environment, such reactions could serve as redox indicators. Formation of RNOS by metal-mediated pathways would confine the chemistry of these species to specific cellular sites. Additionally, such mechanisms would be independent both of NO and NOS, thus increasing the lifetime of RNOS that react with NO. Thus metal-mediated conversion of nitrite, NOHA, and NH(2)OH into biologically active agents may provide a unique signaling mechanism. In this review, we discuss the biochemistry of such reactions in the context of their pharmacologic and biologic implications.
- Published
- 2006
- Full Text
- View/download PDF
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