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Electrophilic adduction of ubiquitin activating enzyme E1 by N,N-diethyldithiocarbamate inhibits ubiquitin activation and is accompanied by striatal injury in the rat.
Viquez OM, Caito SW, McDonald WH, Friedman DB, Valentine WM
(2012) Chem Res Toxicol 25: 2310-21
MeSH Terms: Animals, Corpus Striatum, Ditiocarb, Enzyme Activation, Enzyme Inhibitors, Humans, Male, Models, Molecular, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Ubiquitin-Activating Enzymes
Show Abstract · Added March 20, 2014
Previous studies have shown ubiquitin activating enzyme E1 to be sensitive to adduction through both Michael addition and SN(2) chemistry in vitro. E1 presents a biologically important putative protein target for adduction due to its role in initiating ubiquitin based protein processing and the involvement of impaired ubiquitin protein processing in two types of familial Parkinson's disease. We tested whether E1 is susceptible to xenobiotic-mediated electrophilic adduction in vivo and explored the potential contribution of E1 adduction to neurodegenerative events in an animal model. N,N-Diethyldithiocarbamate (DEDC) was administered to rats using a protocol that produces covalent cysteine modifications in vivo, and brain E1 protein adducts were characterized and mapped using shotgun LC-MS/MS. E1 activity, global and specific protein expression, and protein carbonyls were used to characterize cellular responses and injury in whole brain and dorsal striatal samples. The data demonstrate that DEDC treatment produced S-(ethylaminocarbonyl) adducts on Cys234 and Cys179 residues of E1 and decreased the levels of activated E1 and total ubiquitinated proteins. Proteomic analysis of whole brain samples identified expression changes for proteins involved in myelin structure, antioxidant response, and catechol metabolism, systems often disrupted in neurodegenerative disease. Our studies also delineated localized injury within the striatum as indicated by decreased levels of tyrosine hydroxylase, elevated protein carbonyl content, increased antioxidant enzyme and α-synuclein expression, and enhanced phosphorylation of tau and tyrosine hydroxylase. These data are consistent with E1 having similar susceptibility to adduction in vivo as previously reported in vitro and support further investigation into environmental agent adduction of E1 as a potential contributing factor to neurodegenerative disease. Additionally, this study supports the predictive value of in vitro screens for identifying sensitive protein targets that can be used to guide subsequent in vivo experiments.
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12 MeSH Terms
Peripheral nerve and brain differ in their capacity to resolve N,N-diethyldithiocarbamate-mediated elevations in copper and oxidative injury.
Valentine HL, Viquez OM, Valentine WM
(2010) Toxicology 274: 10-7
MeSH Terms: Animals, Blotting, Western, Brain, Copper, Ditiocarb, Glutathione Transferase, Heme Oxygenase-1, Liver, Male, Mass Spectrometry, Myelin Sheath, Oxidation-Reduction, Oxidative Stress, Peripheral Nerves, Rats, Rats, Sprague-Dawley, Sciatic Nerve, Spinal Cord, Superoxide Dismutase, Superoxide Dismutase-1
Show Abstract · Added May 27, 2014
Previous studies have demonstrated that N,N-diethyldithiocarbamate (DEDC) elevates copper and promotes oxidative stress within the nervous system. However, whether these effects resolve following cessation of exposure or have the potential to persist and result in cumulative injury has not been determined. In this study, an established model for DEDC myelin injury in the rat was used to determine whether copper levels, oxidative stress, and neuromuscular deficits resolve following the cessation of DEDC exposure. Rats were exposed to DEDC for 8 weeks and then either euthanized or maintained for 2, 6 or 12 weeks after cessation of exposure. At each time point copper levels were measured by inductively coupled mass spectrometry to assess the ability of sciatic nerve, brain, spinal cord and liver to eliminate excess copper post-exposure. The protein expression levels of glutathione transferase alpha, heme oxygenase 1 and superoxide dismutase 1 in peripheral nerve and brain were also determined by western blot to assess levels of oxidative stress as a function of post-exposure duration. As an initial assessment of the bioavailability of the excess copper in brain the protein expression levels of copper chaperone for superoxide dismutase 1, and prion protein were determined by western blot as a function of exposure and post-exposure duration. Neuromuscular function in peripheral nerve was evaluated using grip strengths, nerve conduction velocities, and morphologic changes at the light microscope level. The data demonstrated that in peripheral nerve, copper levels and oxidative stress return to control levels within several weeks after cessation of exposure. Neuromuscular function also showed a trend towards pre-exposure values, although the resolution of myelin lesions was more delayed. In contrast, total copper and antioxidant enzyme levels remained significantly elevated in brain for longer post-exposure periods. The persistence of effects observed in brain suggests that the central nervous system is more susceptible to long-term cumulative adverse effects from dithiocarbamates. Additionally, significant changes in expression levels of chaperone for superoxide dismutase 1, and prion protein were observed consistent with at least a portion of the excess copper being bioactive.
2010 Elsevier Ireland Ltd. All rights reserved.
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20 MeSH Terms
N,N-diethyldithiocarbamate promotes oxidative stress prior to myelin structural changes and increases myelin copper content.
Viquez OM, Lai B, Ahn JH, Does MD, Valentine HL, Valentine WM
(2009) Toxicol Appl Pharmacol 239: 71-9
MeSH Terms: Animals, Blotting, Western, Brain, Copper, Ditiocarb, Glutathione Transferase, Heme Oxygenase (Decyclizing), Isoenzymes, Lipid Peroxidation, Male, Microscopy, Fluorescence, Myelin Sheath, Oxidative Stress, Proteasome Endopeptidase Complex, Protein Carbonylation, Rats, Rats, Sprague-Dawley, Sciatic Nerve, Spinal Cord, Superoxide Dismutase, Superoxide Dismutase-1
Show Abstract · Added May 27, 2014
Dithiocarbamates are a commercially important class of compounds that can produce peripheral neuropathy in humans and experimental animals. Previous studies have supported a requirement for copper accumulation and enhanced lipid peroxidation in dithiocarbamate-mediated myelinopathy. The study presented here extends previous investigations in two areas. Firstly, although total copper levels have been shown to increase within the nerve it has not been determined whether copper is increased within the myelin compartment, the primary site of lesion development. Therefore, the distribution of copper in sciatic nerve was characterized using synchrotron X-ray fluorescence microscopy to determine whether the neurotoxic dithiocarbamate, N,N-diethyldithiocarbamate, increases copper levels in myelin. Secondly, because lipid peroxidation is an ongoing process in normal nerve and the levels of lipid peroxidation products produced by dithiocarbamate exposure demonstrated an unusual cumulative dose response in previous studies the biological impact of dithiocarbamate-mediated lipid peroxidation was evaluated. Experiments were performed to determine whether dithiocarbamate-mediated lipid peroxidation products elicit an antioxidant response through measuring the protein expression levels of three enzymes, superoxide dismutase 1, heme oxygenase 1, and glutathione transferase alpha, that are linked to the antioxidant response element promoter. To establish the potential of oxidative injury to contribute to myelin injury the temporal relationship of the antioxidant response to myelin injury was determined. Myelin structure in peripheral nerve was assessed using multi-exponential transverse relaxation measurements (MET(2)) as a function of exposure duration, and the temporal relationship of protein expression changes relative to the onset of changes in myelin integrity were determined. Initial assessments were also performed to explore the potential contribution of dithiocarbamate-mediated inhibition of proteasome function and inhibition of cuproenzyme activity to neurotoxicity, and also to assess the potential of dithiocarbamates to promote oxidative stress and injury within the central nervous system. These evaluations were performed using an established model for dithiocarbamate-mediated demyelination in the rat utilizing sciatic nerve, spinal cord and brain samples obtained from rats exposed to N,N-diethyldithiocarbamate (DEDC) by intra-abdominal pumps for periods of 2, 4, and 8 weeks and from non exposed controls. The data supported the ability of DEDC to increase copper within myelin and to enhance oxidative stress prior to structural changes detectable by MET(2). Evidence was also obtained that the excess copper produced by DEDC in the central nervous system is redox active and promotes oxidative injury.
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21 MeSH Terms
Nitrogen substituent polarity influences dithiocarbamate-mediated lipid oxidation, nerve copper accumulation, and myelin injury.
Valentine HL, Viquez OM, Amarnath K, Amarnath V, Zyskowski J, Kassa EN, Valentine WM
(2009) Chem Res Toxicol 22: 218-26
MeSH Terms: Animals, Copper, Demyelinating Diseases, Ditiocarb, Ethylenebis(dithiocarbamates), Lipid Peroxidation, Male, Malondialdehyde, Mass Spectrometry, Myelin Sheath, Nitrogen, Oxidative Stress, Peripheral Nerves, Rats, Rats, Sprague-Dawley, Sarcosine, Thiocarbamates
Show Abstract · Added May 27, 2014
Dithiocarbamates have a wide spectrum of applications in industry, agriculture, and medicine, with new applications being investigated. Past studies have suggested that the neurotoxicity of some dithiocarbamates may result from copper accumulation, protein oxidative damage, and lipid oxidation. The polarity of a dithiocarbamate's nitrogen substituents influences the lipophilicity of the copper complexes that it generates and thus potentially determines its ability to promote copper accumulation within nerve and induce myelin injury. In the current study, a series of dithiocarbamate-copper complexes differing in their lipophilicity were evaluated for their relative abilities to promote lipid peroxidation determined by malondialdehyde levels generated in an ethyl arachidonate oil-in-water emulsion. In a second component of this study, rats were exposed to either N,N-diethyldithiocarbamate or sarcosine dithiocarbamate; both generated dithiocarbamate-copper complexes that were lipid- and water-soluble, respectively. Following the exposures, brain, tibial nerve, spinal cord, and liver tissue copper levels were measured by inductively coupled mass spectroscopy to assess the relative abilities of these two dithiocarbamates to promote copper accumulation. Peripheral nerve injury was evaluated using grip strengths, nerve conduction velocities, and morphologic changes at the light microscope level. Additionally, the protein expression levels of glutathione transferase alpha and heme-oxygenase-1 in nerve were determined, and the quantity of protein carbonyls was measured to assess levels of oxidative stress and injury. The data provided evidence that dithiocarbamate-copper complexes are redox active and that the ability of dithiocarbamate complexes to promote lipid peroxidation is correlated to the lipophilicity of the complex. Consistent with neurotoxicity requiring the formation of a lipid-soluble copper complex, significant increases in copper accumulation, oxidative stress, and myelin injury were produced by N,N-diethyldithiocarbamate but not by sarcosine dithiocarbamate.
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17 MeSH Terms
Copper accumulation and lipid oxidation precede inflammation and myelin lesions in N,N-diethyldithiocarbamate peripheral myelinopathy.
Viquez OM, Valentine HL, Amarnath K, Milatovic D, Valentine WM
(2008) Toxicol Appl Pharmacol 229: 77-85
MeSH Terms: Animals, Brain, Chelating Agents, Chromatography, High Pressure Liquid, Copper, Demyelinating Diseases, Disease Models, Animal, Ditiocarb, Immunoglobulin G, Lipid Peroxidation, Liver, Macrophage Activation, Macrophages, Male, Malondialdehyde, Mass Spectrometry, Oxidative Stress, Rats, Rats, Sprague-Dawley, Sciatic Nerve, Tibial Nerve
Show Abstract · Added May 27, 2014
Dithiocarbamates have a wide spectrum of applications in industry, agriculture and medicine with new applications being actively investigated. One adverse effect of dithiocarbamates is the neurotoxicity observed in humans and experimental animals. Results from previous studies have suggested that dithiocarbamates elevate copper and promote lipid oxidation within myelin membranes. In the current study, copper levels, lipid oxidation, protein oxidative damage and markers of inflammation were monitored as a function of N,N-diethyldithiocarbamate (DEDC) exposure duration in an established model for DEDC-mediated myelinopathy in the rat. Intra-abdominal administration of DEDC was performed using osmotic pumps for periods of 2, 4, and 8 weeks. Metals in brain, liver and tibial nerve were measured using ICP-MS and lipid oxidation assessed through HPLC measurement of malondialdehyde in tibial nerve, and GC/MS measurement of F(2) isoprostanes in sciatic nerve. Protein oxidative injury of sciatic nerve proteins was evaluated through quantification of 4-hydroxynonenal protein adducts using immunoassay, and inflammation monitored by quantifying levels of IgGs and activated macrophages using immunoassay and immunohistochemistry methods, respectively. Changes in these parameters were then correlated to the onset of structural lesions, determined by light and electron microscopy, to delineate the temporal relationship of copper accumulation and oxidative stress in peripheral nerve to the onset of myelin lesions. The data provide evidence that DEDC mediates lipid oxidation and elevation of total copper in peripheral nerve well before myelin lesions or activated macrophages are evident. This relationship is consistent with copper-mediated oxidative stress contributing to the myelinopathy.
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21 MeSH Terms
ESR techniques for the detection of nitric oxide in vivo as an index of endothelial function.
Fink B, Dikalov S, Fink N
(2006) Pharmacol Rep 58 Suppl: 8-15
MeSH Terms: Adrenergic beta-Antagonists, Animals, Aorta, Carbazoles, Cardiovascular Diseases, Carvedilol, Cattle, Cells, Cultured, Colloids, Ditiocarb, Electron Spin Resonance Spectroscopy, Endothelial Cells, Endothelium, Vascular, Ferrous Compounds, Hemoglobins, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Nitric Oxide, Nitric Oxide Donors, Nitric Oxide Synthase Type III, Nitroglycerin, Propanolamines, Reactive Oxygen Species, Stress, Mechanical
Show Abstract · Added February 17, 2016
Plasma nitrite/nitrate levels reflect oxidation of formed nitric oxide (NO ) but are not indicative of endothelial nitric oxide synthase (eNOS) function due to interference by dietary nitrates and reactive oxygen species (ROS). Nitrosyl hemoglobin (NOHb), a metabolic product of nitric oxide, may better correlate with bioavailable NO but it may depend on the activity of different nitric oxide synthase (NOS) isoforms and may be affected by dietary nitrite/nitrate. We examined the correlation between vascular endothelial NO release and circulating blood levels of NOHb. We measured NOHb in blood using electron spin resonance (ESR) spectrometry and also quantified vascular production of NO using colloid Fe(DETC)(2) and ESR in mouse and human venous blood before and after treatment with the beta-blocker carvedilol. Exclusively the inhibition with L-NAME and not the treatment with the selective neuronal nitric oxide synthase (nNOS) inhibitor, N-AANG or with the selective inducible nitric oxide synthase (iNOS) inhibitor, 1400W, halved NOHb formation, which reflects the complete inhibition of NO release by aortic endothelium. The relationship between NOHb and NO production by the endothelium (0.23 microM NOHb to 3.73 microM/hour of NO per mg of aorta dry weight) was found to be identical for both C57Blk/6 mice and for mice with vascular smooth muscle-targeted expression of p22phox associated with strong increase in eNOS activity. Furthermore, the treatment of patients with cardiovascular diseases with carvedilol for 3 weeks increases up to 2 times the circulating NOHb concentration. These results demonstrate the important role of eNOS in the formation of circulating NOHb and suggest that NOHb can be used as a noninvasive marker of endothelial NO production in vivo.
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28 MeSH Terms
Peripheral nerve protein expression and carbonyl content in N,N-diethlydithiocarbamate myelinopathy.
Viquez OM, Valentine HL, Friedman DB, Olson SJ, Valentine WM
(2007) Chem Res Toxicol 20: 370-9
MeSH Terms: Animals, Chromatography, High Pressure Liquid, Databases, Factual, Demyelinating Diseases, Ditiocarb, Electrophoresis, Polyacrylamide Gel, Fluoresceins, Fluorescent Dyes, Globins, Immunoassay, Immunohistochemistry, Male, Nerve Tissue Proteins, Neural Networks (Computer), Neural Pathways, Oxidative Stress, Peripheral Nervous System, Rats, Rats, Sprague-Dawley, Sciatic Nerve, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Weight Gain
Show Abstract · Added May 27, 2014
Human exposure to dithiocarbamates results from their uses as pesticides, in manufacturing, and as pharmaceutical agents. Neurotoxicity is an established hazard of dithiocarbamate exposure and has been observed in both humans and experimental animals. Previous studies have shown that the neurotoxicity of certain dithiocarbamates, including N,N-diethyldithiocarbamate (DEDC), disulfiram, and pyrrolidine dithiocarbamate, can manifest as a primary myelinopathy of peripheral nerves. Because increased levels of copper in peripheral nerves and elevated levels of lipid peroxidation products accompany DEDC-induced lesions, it has been suggested that the disruption of copper homeostasis and increased oxidative stress may contribute to myelin injury. To further assess the biological impact of DEDC-mediated lipid peroxidation in nerves, the changes in protein expression levels resulting from DEDC exposure were determined. In addition, protein carbonyl content in peripheral nerves was also determined as an initial assessment of protein oxidative damage in DEDC neuropathy. Rats were exposed to DEDC by intra-abdominal osmotic pumps for eight weeks and proteins extracted from the sciatic nerves of DEDC-exposed animals and from non-exposed controls. The comparison of protein expression levels using two-dimensional difference gel electrophoresis demonstrated significant changes in 56 spots of which 46 were identified by MALDI-TOF/MS. Among the proteins showing increased expression were three isoforms of glutathione transferase, important for the detoxification of reactive alpha,beta-unsaturated aldehydes generated from lipid peroxidation. The increased expression of one isoform, glutathione transferase pi, was localized to the cytoplasm of Schwann cells using immunohistochemistry. An immunoassay for nerve protein carbonyls demonstrated a significant increase of approximately 2-fold for the proteins isolated from DEDC-exposed rats. These data support the ability of DEDC to promote protein oxidative damage in peripheral nerves and to produce sufficient lipid peroxidation in either myelin or another component of the Schwann cell to elicit a protective cellular response to oxidative stress.
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22 MeSH Terms
N,N-diethyldithiocarbamate produces copper accumulation, lipid peroxidation, and myelin injury in rat peripheral nerve.
Tonkin EG, Valentine HL, Milatovic DM, Valentine WM
(2004) Toxicol Sci 81: 160-71
MeSH Terms: Alcohol Deterrents, Animals, Chelating Agents, Chromatography, High Pressure Liquid, Copper, Diet, Disulfiram, Ditiocarb, Gas Chromatography-Mass Spectrometry, Histocytochemistry, Isoprostanes, Lipid Peroxidation, Liver, Liver Function Tests, Male, Muscle, Skeletal, Myelin Sheath, Neuromuscular Junction, Peripheral Nerves, Rats, Rats, Sprague-Dawley, Silver Staining, Spectrophotometry, Atomic, Tissue Distribution, Weight Gain
Show Abstract · Added May 27, 2014
Previous studies have demonstrated the ability of the dithiocarbamate, disulfiram, to produce a peripheral neuropathy in humans and experimental animals and have also provided evidence that N,N-diethyldithiocarbamate (DEDC) is a proximate toxic species of disulfiram. The ability of DEDC to elevate copper levels in the brain suggests that it may also elevate levels of copper in peripheral nerve, possibly leading to oxidative stress and lipid peroxidation from redox cycling of copper. The study presented here investigates the potential of DEDC to promote copper accumulation and lipid peroxidation in peripheral nerve. Rats were administered either DEDC or deionized water by ip osmotic pumps and fed a normal diet or diet containing elevated copper, and the levels of metals, isoprostanes, and the severity of lesions in peripheral nerve and brain were assessed by ICP-AES/AAS, GC/MS, and light microscopy, respectively. Copper was the only metal that demonstrated any significant compound-related elevations relative to controls, and total copper was increased in both brain and peripheral nerve in animals administered DEDC on both diets. In contrast, lesions and elevated F2-isoprostanes were significantly increased only in peripheral nerve for the rats administered DEDC on both diets. Autometallography staining of peripheral nerve was consistent with increased metal content along the myelin sheath, but in brain, focal densities were observed, and a periportal distribution occurred in liver. These data are consistent with the peripheral nervous system being more sensitive to DEDC-mediated demyelination and demonstrate the ability of DEDC to elevate copper levels in peripheral nerve. Additionally lipid peroxidation appears to either be a contributing event in the development of demyelination, possibly through an increase of redox active copper, or a consequence of the myelin injury.
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25 MeSH Terms
Parenteral N,N-diethyldithiocarbamate produces segmental demyelination in the rat that is not dependent on cysteine carbamylation.
Tonkin EG, Valentine HL, Zimmerman LJ, Valentine WM
(2003) Toxicol Appl Pharmacol 189: 139-50
MeSH Terms: Animals, Body Weight, Chelating Agents, Chromatography, High Pressure Liquid, Cysteine, Demyelinating Diseases, Ditiocarb, Globins, Infusion Pumps, Implantable, Infusions, Parenteral, Male, Neurofilament Proteins, Peripheral Nerves, Rats, Rats, Sprague-Dawley
Show Abstract · Added May 27, 2014
Disulfiram, a dithiocarbamate drug used in alcohol aversion therapy, produces a peripheral neuropathy characterized in rats as segmental demyelination accompanied by generation of S-(diethylaminocarbonyl)cysteine (DETC-Cys) adducts. N,N-Diethyldithiocarbamate (DEDC) is a major metabolite of disulfiram that can undergo methylation and oxidation to S-methyl-N,N-diethylthiocarbamate (MeDETC) sulfoxide and sulfone, thought to be responsible for carbamylation of sulfhydryl functions by disulfiram. To assess the role of cysteine carbamylation in disulfiram toxicity, DEDC and MeDETC were administered parenterally to male Sprague-Dawley rats for 4 and 8 weeks. The roles of the disulfide linkage in disulfiram and of carbamylated glutathione metabolites were assessed by administering S-(diethylaminodithiocarbonyl)N-acetylcysteine (DS-NAC) and S-(diethylaminocarbonyl)-N-acetylcysteine (DETC-NAC), respectively, parenterally for 12 weeks. Following exposure, spinal cord-derived neurofilament preparations and hemoglobin were isolated and analyzed by RP-HPLC and LC/MS/MS for the presence of DETC-Cys adducts. Peripheral nerve sections were also obtained and examined by light and electron microscopy for morphological lesions. RP-HPLC analysis of globin preparations from DEDC-, MeDETC-, and DS-NAC-exposed animals demonstrated a late-eluting peak, identical to that reported for disulfiram-generated DETC-Cys adducts on the beta(3)-globin chain. DETC-NAC exposure did not result in detectable globin modification by RP-HPLC. The quantity of DETC-Cys adducts produced on globin and neurofilament preparations determined by LC/MS/MS was twofold greater for MeDETC than DEDC following equimolar doses of each compound. Primary myelin lesions consisting of demyelinated axons and myelin splitting were observed in peripheral nerves following exposure to DEDC for 8 weeks. No lesions were detected following exposure to MeDETC, DS-NAC, or DETC-NAC at any time point or dose level. These results are consistent with DEDC, but not the other metabolites, being a demyelinating agent and thus a potential proximate toxic species for disulfiram-mediated demyelination. The production of significantly greater levels of DETC-Cys adducts by MeDETC relative to DEDC in the absence of neurotoxicity for MeDETC is consistent with cysteine carbamylation not contributing to the demyelination produced by disulfiram and DEDC.
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15 MeSH Terms
Inhibition of copper-zinc superoxide dismutase induces cell growth, hypertrophic phenotype, and apoptosis in neonatal rat cardiac myocytes in vitro.
Siwik DA, Tzortzis JD, Pimental DR, Chang DL, Pagano PJ, Singh K, Sawyer DB, Colucci WS
(1999) Circ Res 85: 147-53
MeSH Terms: Animals, Animals, Newborn, Apoptosis, Cardiomegaly, Cell Division, Cell Membrane, Cells, Cultured, Chelating Agents, Ditiocarb, Gene Expression Regulation, Enzymologic, Hypertrophy, In Situ Nick-End Labeling, In Vitro Techniques, Muscle Fibers, Skeletal, Myocardium, Oxidative Stress, Phenotype, Rats, Superoxide Dismutase, Superoxides
Show Abstract · Added March 5, 2014
Oxidative stress has been implicated in the pathophysiology of myocardial failure. We tested the hypothesis that inhibition of endogenous antioxidant enzymes can regulate the phenotype of cardiac myocytes. Neonatal rat ventricular myocytes in vitro were exposed to diethyldithiocarbamic acid (DDC), an inhibitor of cytosolic (Cu, Zn) and extracellular superoxide dismutase (SOD). DDC inhibited SOD activity and increased intracellular superoxide in a concentration-dependent manner. A low concentration (1 micromol/L) of DDC stimulated myocyte growth, as demonstrated by increases in protein synthesis, cellular protein, prepro-atrial natriuretic peptide, and c-fos mRNAs and decreased sarcoplasmic reticulum Ca(2+)ATPase mRNA. These actions were all inhibited by the superoxide scavenger Tiron (4,5-dihydroxy-1,3-benzene disulfonic acid). Higher concentrations of DDC (100 micromol/L) stimulated myocyte apoptosis, as evidenced by DNA laddering, characteristic nuclear morphology, in situ terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL), and increased bax mRNA expression. DDC-stimulated apoptosis was inhibited by the SOD/catalase mimetic EUK-8. The growth and apoptotic effects of DDC were mimicked by superoxide generation with xanthine plus xanthine oxidase. Thus, increased intracellular superoxide resulting from inhibition of SOD causes activation of a growth program and apoptosis in cardiac myocytes. These findings support a role for oxidative stress in the pathogenesis of myocardial remodeling and failure.
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20 MeSH Terms