scholarly journals Structural basis of mitochondrial dysfunction in response to cytochrome c phosphorylation at tyrosine 48

2017 ◽  
Vol 114 (15) ◽  
pp. E3041-E3050 ◽  
Author(s):  
Blas Moreno-Beltrán ◽  
Alejandra Guerra-Castellano ◽  
Antonio Díaz-Quintana ◽  
Rebecca Del Conte ◽  
Sofía M. García-Mauriño ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Molecular Basis ◽  
Structural Basis ◽  
Mitochondrial Activity ◽  
Oxygen Species ◽  
Therapeutic Approaches ◽  
Mitochondrial Signaling ◽  
Novel Therapeutic ◽  
Carboxy Methyl

Regulation of mitochondrial activity allows cells to adapt to changing conditions and to control oxidative stress, and its dysfunction can lead to hypoxia-dependent pathologies such as ischemia and cancer. Although cytochrome c phosphorylation—in particular, at tyrosine 48—is a key modulator of mitochondrial signaling, its action and molecular basis remain unknown. Here we mimic phosphorylation of cytochrome c by replacing tyrosine 48 with p-carboxy-methyl-l-phenylalanine (pCMF). The NMR structure of the resulting mutant reveals significant conformational shifts and enhanced dynamics around pCMF that could explain changes observed in its functionality: The phosphomimetic mutation impairs cytochrome c diffusion between respiratory complexes, enhances hemeprotein peroxidase and reactive oxygen species scavenging activities, and hinders caspase-dependent apoptosis. Our findings provide a framework to further investigate the modulation of mitochondrial activity by phosphorylated cytochrome c and to develop novel therapeutic approaches based on its prosurvival effects.

Flavonoids, the Family of Plant-derived Antioxidants making inroads into Novel Therapeutic Design against IR-induced Oxidative Stress in Parkinson’s Disease

2021 ◽  
Vol 19 ◽  
Author(s):  
Tapan Behl ◽  
Gagandeep Kaur ◽  
Aayush Sehgal ◽  
Gokhan Zengin ◽  
Sukhbir Singh ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ionizing Radiation ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Radiation Induced ◽  
Novel Therapeutic

Background: Ionizing radiation from telluric sources is unceasingly an unprotected pitfall to humans. Thus, the foremost contributors to human exposure are global and medical radiations. Various pieces of evidences assembled during preceding years reveal the pertinent role of ionizing radiation-induced oxidative stress in the progression of neurodegenerative insults such as Parkinson’s disease, which have been contributing to increased proliferation and generation of reactive oxygen species. Objective: This review delineates the role of ionizing radiation-induced oxidative stress in Parkinson’s disease and proposes novel therapeutic interventions of flavonoid family offering effective management and slowing down the progression of Parkinson’s disease. Method: Published papers were searched via MEDLINE, PubMed, etc. published to date for in-depth database collection. Results: The potential of oxidative damage may harm the non-targeted cells. It can also modulate the functions of central nervous system, such as protein misfolding, mitochondria dysfunction, increased levels of oxidized lipids, and dopaminergic cell death, which accelerates the progression of Parkinson’s disease at the molecular, cellular, or tissue levels. In Parkinson’s disease, reactive oxygen species exacerbate the production of nitric oxides and superoxides by activated microglia, rendering death of dopaminergic neuronal cell through different mechanisms. Conclusion: Rising interest has extensively engrossed on the clinical trial designs based on the plant derived family of antioxidants. They are known to exert multifarious impact either way in neuroprotection via directly suppressing ionizing radiation-induced oxidative stress and reactive oxygen species production or indirectly increasing the dopamine levels and activating the glial cells.

scholarly journals Piceatannol Increases Antioxidant Defense and Reduces Cell Death in Human Periodontal Ligament Fibroblast under Oxidative Stress

Antioxidants ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 16 ◽  
Author(s):  
Flávia Póvoa da Costa ◽  
Bruna Puty ◽  
Lygia S. Nogueira ◽  
Geovanni Pereira Mitre ◽  
Sávio Monteiro dos Santos ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Cell Death ◽  
Cell Viability ◽  
Antioxidant Capacity ◽  
Periodontal Ligament ◽  
Cellular Metabolism ◽  
Mitochondrial Activity ◽  
Oxygen Species ◽  
Atp Production

Piceatannol is a resveratrol metabolite that is considered a potent antioxidant and cytoprotector because of its high capacity to chelate/sequester reactive oxygen species. In pathogenesis of periodontal diseases, the imbalance of reactive oxygen species is closely related to the disorder in the cells and may cause changes in cellular metabolism and mitochondrial activity, which is implicated in oxidative stress status or even in cell death. In this way, this study aimed to evaluate piceatannol as cytoprotector in culture of human periodontal ligament fibroblasts through in vitro analyses of cell viability and oxidative stress parameters after oxidative stress induced as an injury simulator. Fibroblasts were seeded and divided into the following study groups: control, vehicle, control piceatannol, H2O2 exposure, and H2O2 exposure combined with the maintenance in piceatannol ranging from 0.1 to 20 μM. The parameters analyzed following exposure were cell viability by trypan blue exclusion test, general metabolism status by the 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) method, mitochondrial activity through the ATP production, total antioxidant capacity, and reduced gluthatione. Piceatannol was shown to be cytoprotective due the maintenance of cell viability between 1 and 10 μM even in the presence of H2O2. In a concentration of 0.1 μM piceatannol decreased significantly cell viability but increased cellular metabolism and antioxidant capacity of the fibroblasts. On the other hand, the fibroblasts treated with piceatannol at 1 μM presented low metabolism and antioxidant capacity. However, piceatannol did not protect cells from mitochondrial damage as measured by ATP production. In summary, piceatannol is a potent antioxidant in low concentrations with cytoprotective capacity, but it does not prevent all damage caused by hydrogen peroxide.

scholarly journals Redox Regulation and Oxidative Stress: The Particular Case of the Stallion Spermatozoa

Antioxidants ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 567 ◽  
Author(s):  
Fernando J. Peña ◽  
Cristian O’Flaherty ◽  
José M. Ortiz Rodríguez ◽  
Francisco E. Martín Cano ◽  
Gemma L. Gaitskell-Phillips ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Redox Regulation ◽  
Redox Homeostasis ◽  
Reactive Oxygen ◽  
Mitochondrial Activity ◽  
Oxygen Species ◽  
Redox Biology ◽  
Major Interest ◽  
And Oxidative Stress

Redox regulation and oxidative stress have become areas of major interest in spermatology. Alteration of redox homeostasis is recognized as a significant cause of male factor infertility and is behind the damage that spermatozoa experience after freezing and thawing or conservation in a liquid state. While for a long time, oxidative stress was just considered an overproduction of reactive oxygen species, nowadays it is considered as a consequence of redox deregulation. Many essential aspects of spermatozoa functionality are redox regulated, with reversible oxidation of thiols in cysteine residues of key proteins acting as an “on–off” switch controlling sperm function. However, if deregulation occurs, these residues may experience irreversible oxidation and oxidative stress, leading to malfunction and ultimately death of the spermatozoa. Stallion spermatozoa are “professional producers” of reactive oxygen species due to their intense mitochondrial activity, and thus sophisticated systems to control redox homeostasis are also characteristic of the spermatozoa in the horse. As a result, and combined with the fact that embryos can easily be collected in this species, horses are a good model for the study of redox biology in the spermatozoa and its impact on the embryo.

242 PROTECTIVE EFFECT OF VITAMIN E TREATMENT IN HEAT-STRESSED BOS TAURUS BULLS

2013 ◽  
Vol 25 (1) ◽  
pp. 269 ◽  
Author(s):  
V. H. Barnabe ◽  
R. C. Barnabe ◽  
P. Goes ◽  
E. G. A. Perez ◽  
J. D. A. Losano ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Heat Stress ◽  
Vitamin E ◽  
Bos Taurus ◽  
Semen Quality ◽  
Reactive Oxygen ◽  
Mitochondrial Activity ◽  
Oxygen Species ◽  
Tropical Conditions

Bos taurus bulls, when raised under tropical conditions, are highly susceptible to heat stress, which leads to impaired semen quality, leading to significant economical losses because, in these regions, the reproductive mounting season occurs mainly during the summer. Previous studies have indicated that oxidative stress (i.e. attack by reactive oxygen species) may be the main mechanism of sperm damage in such conditions. Therefore, treatment with antioxidants may be an important alternative to improve semen quality in heat-stressed B. taurus bulls. The objective of the present study was to evaluate whether the treatment with vitamin E, an important antioxidant, could improve sperm quality in insulated bulls. Towards this aim, eight adult Holstein bulls were submitted for semen collection, and the sperm was submitted for motility evaluation by computer-assisted sperm analysis (Ivos, Hamilton Thorne Inc., Beverly, MA, USA), examination of membrane and acrosomal integrity (eosin/nigrosin and fast green/bengal rose stain, respectively), mitochondrial activity (diaminobenzidine stain; full mitochondrial activity or no mitochondrial activity), and sperm susceptibility to oxidative stress (thiobarbituric acid-reactive substances). Bulls were then insulated (testicles covered in a thermal bag for 3 days) and randomly assigned to two treatment groups: no vitamin E (placebo) and vitamin E (subcutaneous injection of 3000 IU of α-tocopherol each of 10 days). Subsequent semen analysis was performed 1 and 60 days after the insulation. Statistical analysis was performed with SAS (SAS Institute Inc., Cary, NC, USA) repeated-measures ANOVA, and significance of P < 0.05 was adopted. No differences were found on any of the variables before insulation. One day after insulation, animals treated with vitamin E showed a lower percentage of static sperm and a higher percentage of motile sperm when compared with animals treated with the placebo (28 and 63% v. 56 and 34%, respectively; P < 0.05). Also at this time, sperm susceptibility to oxidative stress was lower in animals treated with vitamin E (vitamin E: 410 ng/106 sperm; no vitamin E: 1760 ng/106 sperm; P < 0.05). Sixty days after insulation, sperm susceptibility to oxidative stress was still lower in animals treated with vitamin E when compared with the placebo group (1176 and 192 ng/106 sperm, respectively; P < 0.05). However, no differences were found on the other variables. Results indicate that vitamin E, an antioxidant whose main function is protection of the plasma membrane, may be an alternative to avoid the acute deleterious effects of the heat stress in B. taurus bulls raised under tropical conditions. In addition, even with no heat stress involved, vitamin E treatment may provide constant protection, increasing the resistance of the sperm against the reactive oxygen species.

scholarly journals Photobiomodulation and Oxidative Stress: 980 nm Diode Laser Light Regulates Mitochondrial Activity and Reactive Oxygen Species Production

2021 ◽  
Vol 2021 ◽  
pp. 1-11 ◽  
Author(s):  
Andrea Amaroli ◽  
Claudio Pasquale ◽  
Angelina Zekiy ◽  
Anatoliy Utyuzh ◽  
Stefano Benedicenti ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Oxygen Consumption ◽  
Respiratory Chain ◽  
Laser Light ◽  
Krebs Cycle ◽  
Mitochondrial Activity ◽  
Oxygen Species ◽  
Atp Production ◽  
And Oxidative Stress

Photobiomodulation with 808 nm laser light electively stimulates Complexes III and IV of the mitochondrial respiratory chain, while Complexes I and II are not affected. At the wavelength of 1064 nm, Complexes I, III, and IV are excited, while Complex II and some mitochondrial matrix enzymes seem to be not receptive to photons at that wavelength. Complex IV was also activated by 633 nm. The mechanism of action of wavelengths in the range 900–1000 nm on mitochondria is less understood or not described. Oxidative stress from reactive oxygen species (ROS) generated by mitochondrial activity is an inescapable consequence of aerobic metabolism. The antioxidant enzyme system for ROS scavenging can keep them under control. However, alterations in mitochondrial activity can cause an increment of ROS production. ROS and ATP can play a role in cell death, cell proliferation, and cell cycle arrest. In our work, bovine liver isolated mitochondria were irradiated for 60 sec, in continuous wave mode with 980 nm and powers from 0.1 to 1.4 W (0.1 W increment at every step) to generate energies from 6 to 84 J, fluences from 7.7 to 107.7 J/cm2, power densities from 0.13 to 1.79 W/cm2, and spot size 0.78 cm2. The control was equal to 0 W. The activity of the mitochondria’s complexes, Krebs cycle enzymes, ATP production, oxygen consumption, generation of ROS, and oxidative stress were detected. Lower powers (0.1–0.2 W) showed an inhibitory effect; those that were intermediate (0.3–0.7 W) did not display an effect, and the higher powers (0.8–1.1 W) induced an increment of ATP synthesis. Increasing the power (1.2–1.4 W) recovered the ATP production to the control level. The interaction occurred on Complexes III and IV, as well as ATP production and oxygen consumption. Results showed that 0.1 W uncoupled the respiratory chain and induced higher oxidative stress and drastic inhibition of ATP production. Conversely, 0.8 W kept mitochondria coupled and induced an increase of ATP production by increments of Complex III and IV activities. An augmentation of oxidative stress was also observed, probably as a consequence of the increased oxygen consumption and mitochondrial isolation experimental conditions. No effect was observed using 0.5 W, and no effect was observed on the enzymes of the Krebs cycle.

232 INFLUENCE OF SEMINAL PLASMA ON THE SUSCEPTIBILITY OF DOG SPERM AGAINST DIFFERENT REACTIVE OXYGEN SPECIES

2011 ◽  
Vol 23 (1) ◽  
pp. 215
Author(s):  
A. Dalmazzo ◽  
P. A. A. Góes ◽  
M. Nichi ◽  
R. O. C. Silva ◽  
J. R. C. Gurgel ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Lipid Peroxidation ◽  
Hydroxyl Radical ◽  
Seminal Plasma ◽  
Superoxide Anion ◽  
The Other ◽  
Mitochondrial Activity ◽  
Oxygen Species ◽  
Acrosome Integrity

Due to the importance of dogs to humans, there is increasing interest in breeders in the use of reproductive biotechnologies. However, most of the biotechnologies would require the removal or dilution of the seminal plasma, which is known to exert both beneficial and deleterious effects on sperm quality. One of the beneficial effects of seminal plasma would be the antioxidant protection because sperm are particularly susceptible to oxidative stress, mainly due to the reduced cytoplasm and the high content of polyunsaturated fatty acids in their membrane. An alternative to overcome the injuries caused by oxidative stress is the antioxidant treatment, which requires the identification of those reactive oxygen species (ROS) that are the most deleterious. The aim of this study was to identify the most harmful ROS to dog semen. Semen samples from 6 adult dogs were collected and centrifuged. Seminal plasma (SP) was removed and samples were incubated (1 h, 37°C) with 4 ROS-inducing mechanisms: xanthine/xanthine oxidase (produces superoxide anion), hydrogen peroxide (4 mM), ascorbate and ferrous sulfate (4 mM; produces hydroxyl radical) alone or with additional SP. Samples were analysed for motility by computer assisted sperm analysis (CASA). The 3-3′ diaminobenzidine stain was used as an index of mitochondrial activity, the eosin nigrosin stain as an index of membrane integrity, the simple stain (fast green/Bengal rose) as an index of acrosome integrity, sperm chromatin structure assay (SCSA) as an index of DNA fragmentation, and measurement of thiobarbituric acid reactive substances (TBARS) as an index of lipid peroxidation. Statistical analysis was performed using the SAS System for Windows (SAS Institute Inc., Cary, NC, USA; least significant differences test and Spearman correlation; P < 0.05). Results showed that dog sperm is differentially modulated depending on the presence of SP. In addition, damage to the different sperm structures depended on the different ROS. Samples incubated with SP showed no differences concerning TBARS (1 233 in SP, 1 260 in Tris; P = 0.99). On the other hand, samples incubated without SP showed higher lipid peroxidation when treated with hydroxyl radical compared with the other ROS. Furthermore, although hydroxyl radical mostly altered mitochondrial activity in samples incubated with SP (DAB IV = 4.3%; P < 0.05 against all other ROS), the most significant ROS in samples incubated without SP was hydrogen peroxide (DAB IV = 4.7%; P < 0.05 against all other ROS). Superoxide anion was less harmful to acrosome integrity in samples incubated with SP and to motility in samples incubated without SP. The present results suggest that seminal plasma may play an important role in the susceptibility of dog sperm to oxidative stress. Moreover, the results indicate that different sperm compartments are susceptible to different ROS. It is concluded that the quality of frozen–thawed dog semen may be improved by treating with a combination of different antioxidants to destroy the chain reaction causing the oxidative stress. FAPESP is acknowledged for financial support.

93 EFFECT OF ANTIOXIDANTS SUPPLEMENTATION ON THE QUALITY OF CRYOPRESERVED SPERM OF DOGS

2011 ◽  
Vol 23 (1) ◽  
pp. 152
Author(s):  
C. A. B. Sobrinho ◽  
M. Nichi ◽  
P. A. A. Góes ◽  
A. Dalmazzo ◽  
S. E. Crusco ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Vitamin E ◽  
Reactive Oxygen ◽  
The Other ◽  
Mitochondrial Activity ◽  
Enzymatic Antioxidants ◽  
Oxygen Species ◽  
Intact Membrane

One of the main causes of poor quality of frozen–thawed dog sperm is oxidative stress (i.e. higher production of reactive oxygen species not compensated by improved antioxidant protection). This event is known to impair sperm functionality by attacking plasma membrane, acrosome, mitochondria, and DNA. Spermatozoa are particularly susceptible the oxidative stress, mainly due to the reduced cytoplasm and the high content of polyunsaturated fatty acids (PUFA) in the membrane, which allows the spermatozoa to be motile and confers a higher resistance against the damages caused by cryopreservation, but makes the sperm more susceptible to the attack of the reactive oxygen species (ROS). The present study aimed to evaluate the effects of antioxidant supplementation on semen extender (Tris-egg yolk-citrate-glicerol) with glutathione (GSH) and vitamin E on the quality of cryopreserved dog sperm. Ejaculates of 12 dogs were divided in pools of 3 ejaculates with at least 70% of motility. Each pool was diluted with 7 different extenders for treatment groups as follows: control, vitamin E (1, 5, and 10 mM), and reduced glutathione (GSH; 1, 5, and 10 mM) and submitted to cryopreservation. Samples were thawed (37°C/30′) and evaluated for motility, vigor, percentage of sperm showing intact membrane (eosin/nigrosin), and acrosome (simple stain fast-green and bengal rose), mitochondrial activity (3–3′-diaminobenzidine-DAB), and sperm susceptibility to oxidative stress (TBARS). Statistical analyses were performed using the SAS system for Windows (SAS Institute Inc., Cary, NC, USA; least significant differences test and Spearman correlation; P < 0.05). Samples treated with 1 mM of GSH showed a higher percentage of sperm with intact membrane when compared with the control (11.21 ± 2.84 and 6.21 ± 1.16%, respectively; P < 0.05). On the other hand, treatment with 5 mM of GSH showed better results regarding mitochondrial activity. Vitamin E supplementation also played a protective role on mitochondrial activity; samples treated with 1 mM showed a lower percentage of DAB III sperm (cells with severely compromised mitochondrial activity) when compared with the control group (5.61 ± 0.7 and 8.62 ± 1.05%, respectively; P < 0.05). Both vitamin E and GSH are important non-enzymatic antioxidants responsible for the destruction of the hydroxyl radical. Despite the positive influence of these antioxidants on mitochondrial status, no effect was found on the other variables studied. These results indicate that the action of both antioxidants in dog sperm would be mainly intracellular. Furthermore, other ROS could be responsible for the other damages caused by cryopreservation on the other sperm functionalities (i.e. membrane, acrosome, DNA, oxidative status). Therefore, the use of a combination of enzymatic and non-enzymatic antioxidants could be an alternative to overcome the deleterious influence of oxidative stress in cryopreserved semen of dogs. The authors thank the Brazilian army for the dogs used in this study.

scholarly journals Vitamin E Delivery Systems Increase Resistance to Oxidative Stress in Red Deer Sperm Cells: Hydrogel and Nanoemulsion Carriers

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1780
Author(s):  
Alejandro Jurado-Campos ◽  
Pedro Javier Soria-Meneses ◽  
Francisca Sánchez-Rubio ◽  
Enrique Niza ◽  
Iván Bravo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Lipid Peroxidation ◽  
Vitamin E ◽  
Reactive Oxygen ◽  
Mitochondrial Activity ◽  
Sperm Cells ◽  
Oxygen Species ◽  
New Formulation ◽  
Species Production

Oxidative stress has become a major concern in the field of spermatology, and one of the possible solutions to this acute problem would be the use of antioxidant protection; however, more studies are required in this field, as highly contradictory results regarding the addition of antioxidants have been obtained. Vitamin E is a powerful biological antioxidant, but its low stability and high hydrophobicity limit its application in spermatology, making the use of organic solvents necessary, which renders spermatozoa practically motionless. Keeping this in mind, we propose the use of hydrogels (HVEs) and nanoemulsions (NVEs), alone or in combination, as carriers for the controlled release of vitamin E, thus, improving its solubility and stability and preventing oxidative stress in sperm cells. Cryopreserved sperm from six stags was thawed and extended to 30 × 106 sperm/mL in Bovine Gamete Medium (BGM). Once aliquoted, the samples were incubated as follows: control, free vitamin E (1 mM), NVEs (9 mM), HVEs (1 mM), and the combination of HVEs and NVEs (H + N), with or without induced oxidative stress (100 µM Fe2+/ascorbate). The different treatments were analyzed after 0, 2, 5, and 24 h of incubation at 37 °C. Motility (CASA®), viability (YO-PRO-1/IP), mitochondrial membrane potential (Mitotracker Deep Red 633), lipid peroxidation (C11 BODIPY 581/591), intracellular reactive oxygen species production (CM-H2DCFDA), and DNA status (SCSA®) were assessed. Our results show that the deleterious effects of exogenous oxidative stress were prevented by the vitamin E-loaded carriers proposed, while the kinematic sperm parameters (p ˂ 0.05) and sperm viability were always preserved. Moreover, the vitamin E formulations maintained and preserved mitochondrial activity, prevented sperm lipid peroxidation, and decreased reactive oxygen species (ROS) production (p ˂ 0.05) under oxidative stress conditions. Vitamin E formulations were significantly different as regards the free vitamin E samples (p < 0.001), whose sperm kinematic parameters drastically decreased. This is the first time that vitamin E has been formulated as hydrogels. This new formulation could be highly relevant for sperm physiology preservation, signifying an excellent approach against sperm oxidative damage.

Clinical aspects of reactive oxygen and nitrogen species

2004 ◽  
Vol 71 ◽  
pp. 121-133 ◽  
Author(s):  
Ascan Warnholtz ◽  
Maria Wendt ◽  
Michael August ◽  
Thomas Münzel
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Risk Factor ◽  
Endothelial Dysfunction ◽  
Vascular Tissue ◽  
Rapid Development ◽  
Reactive Oxygen ◽  
Clinical Aspects ◽  
No Production ◽  
Oxygen Species

Endothelial dysfunction in the setting of cardiovascular risk factors, such as hypercholesterolaemia, hypertension, diabetes mellitus and chronic smoking, as well as in the setting of heart failure, has been shown to be at least partly dependent on the production of reactive oxygen species in endothelial and/or smooth muscle cells and the adventitia, and the subsequent decrease in vascular bioavailability of NO. Superoxide-producing enzymes involved in increased oxidative stress within vascular tissue include NAD(P)H-oxidase, xanthine oxidase and endothelial nitric oxide synthase in an uncoupled state. Recent studies indicate that endothelial dysfunction of peripheral and coronary resistance and conductance vessels represents a strong and independent risk factor for future cardiovascular events. Ways to reduce endothelial dysfunction include risk-factor modification and treatment with substances that have been shown to reduce oxidative stress and, simultaneously, to stimulate endothelial NO production, such as inhibitors of angiotensin-converting enzyme or the statins. In contrast, in conditions where increased production of reactive oxygen species, such as superoxide, in vascular tissue is established, treatment with NO, e.g. via administration of nitroglycerin, results in a rapid development of endothelial dysfunction, which may worsen the prognosis in patients with established coronary artery disease.

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