Effect of N-acetyl-cysteine on the hypoxic ventilatory response and erythropoietin production: linkage between plasma thiol redox state and O2 chemosensitivity

Hildebrandt, Wulf; Alexander, Steve P.H.; Bärtsch, Peter; Dröge, Wulf

doi:10.1182/blood.v99.5.1552

Cited by 84 publications

(65 citation statements)

References 32 publications

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“…The role of ROS as O 2 messengers has been supported by the finding that, similar to a typical response to hypoxia, treatment of healthy human volunteers with the antioxidant N-acetylcysteine enhanced the hypoxic ventilatory response and erythropoietin (EPO) concentration in blood (6). Thus, N-acetylcysteine or its biochemical derivatives, cysteine, and glutathione mimic hypoxia.…”

mentioning

confidence: 60%

A Fenton reaction at the endoplasmic reticulum is involved in the redox control of hypoxia-inducible gene expression

Liu

Berchner‐Pfannschmidt

Möller

et al. 2004

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

156

113

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It has been proposed that hydroxyl radicals (⅐OH) generated in a perinuclear iron-dependent Fenton reaction are involved in O 2-dependent gene expression. Thus, it was the aim of this study to localize the cellular compartment in which the Fenton reaction takes place and to determine whether scavenging of ⅐OH can modulate hypoxia-inducible factor 1 (HIF-1)-dependent gene expression. The Fenton reaction was localized by using the nonfluorescent dihydrorhodamine (DHR) 123 that is irreversibly oxidized to fluorescent rhodamine 123 while scavenging ⅐OH together with gene constructs allowing fluorescent labeling of mitochondria, endoplasmic reticulum (ER), Golgi apparatus, peroxisomes, or lysosomes. A 3D two-photon confocal laser scanning microscopy showed ⅐OH generation in distinct hot spots of perinuclear ER pockets. This ER-based Fenton reaction was strictly pO 2-dependent.

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mentioning

confidence: 60%

A Fenton reaction at the endoplasmic reticulum is involved in the redox control of hypoxia-inducible gene expression

Liu

Berchner‐Pfannschmidt

Möller

et al. 2004

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

156

113

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“…A highly compartmentalized production of ROS adjacent to target molecules may, in addition, be relatively protected from immediate scavenging, thereby obscuring effects of external manipulations. Nonetheless, oral administration of NAC enhances the hypoxic ventilatory response in humans, suggesting an important role for cellular redox status within at least one of the multiple components comprising the chemoreflex pathway (27). Figure 6 presents a summary of current concepts of O 2 chemoreception in carotid body chemoreceptor type I cells, indicating potential targets for ROS.…”

Section: Discussionmentioning

confidence: 99%

Effect of p47^phoxgene deletion on ROS production and oxygen sensing in mouse carotid body chemoreceptor cells

He¹,

Dinger²,

Sanders³

et al. 2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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. Effect of p47 phox gene deletion on ROS production and oxygen sensing in mouse carotid body chemoreceptor cells. Am J Physiol Lung Cell Mol Physiol 289: L916 -L924, 2005; doi:10.1152/ajplung.00015.2005.-Membrane potential in oxygensensitive type I cells in carotid body is controlled by diverse sets of voltage-dependent and -independent K ϩ channels. Coupling of PO2 to the open-closed state of channels may involve production of reactive oxygen species (ROS) by NADPH oxidase. One hypothesis suggests that ROS are produced in proportion to the prevailing PO 2 and a subset of K ϩ channels closes as ROS levels decrease. We evaluated ROS levels in normal and p47 phox gene-deleted [NADPH oxidase knockout (KO)] type I cells using the ROS-sensitive dye dihydroethidium (DHE). In normal cells, hypoxia elicited an increase in ROS, which was blocked by the specific NADPH oxidase inhibitor 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF, 3 mM). KO type I cells did not respond to hypoxia, but the mitochondrial uncoupler azide (5 M) elicited increased fluorescence in both normal and KO cells. Hypoxia had no effect on ROS production in sensory and sympathetic neurons. Methodological control experiments showed that stimulation of neutrophils with a cocktail containing the chemotactic peptide N-formylMet-Leu-Phe (1 M), arachidonic acid (10 M), and cytochalasin B (5 g/ml) elicited a rapid increase in DHE fluorescence. This response was blocked by the NADPH oxidase inhibitor diphenyleneiodonium (10 M). KO neutrophils did not respond; however, azide (5 M) elicited a rapid increase in fluorescence. Physiological studies in type I cells demonstrated that hypoxia evoked an enhanced depression of K ϩ current and increased intracellular Ca 2ϩ levels in KO vs. normal cells. Moreover, AEBSF potentiated hypoxia-induced increases in intracellular Ca 2ϩ and enhanced the depression of K ϩ current in low O 2. Our findings suggest that local compartmental increases in oxidase activity and ROS production inhibit the activity of type I cells by facilitating K ϩ channel activity in hypoxia.reactive oxygen species; potassium channels; cellular redox; dihydroethidium; cell calcium EXPOSURE OF CAROTID BODY ARTERIAL chemoreceptors to lowered PO 2 elicits increased neural activity in the carotid sinus nerve (CSN) and reflex cardiopulmonary adjustments that mitigate the adverse effects of hypoxemia. Increased carotid body activity occurs at relatively moderate PO 2 levels, in contrast to the severe hypoxia required to elicit metabolic and functional adjustments in non-O 2 -sensing tissues (19,20,23). Efforts to understand the molecular physiology of hypoxic chemotransduction in the carotid body have focused primarily on the relationship between PO 2 and the activity of K ϩ channels in neuroectoderm-derived type I cells (23,40). In the rat, multiple studies have demonstrated that hypoxia inhibits two types of K ϩ channels: 1) a large-conductance, voltage-and calciumdependent channel [maxiK (39, 50)] and 2) a voltage-independent TASK-type channel that me...

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“…The results show a direct correlation between free radicals and circulating biological peroxides and thus provide information about oxidative status. 15,16) Essential hypertension is associated with greater than normal lipoperoxidation and an imbalance in anti-oxidant status, suggesting that oxidative stress is important in the pathogenesis of essential hypertension or in arterial damage related to essential hypertension. 17) Reduced bioavailability of NO or scavenging of NO through oxidative stress appear to be the key processes through which endothelial dysfunction is manifested in hypertension.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic Biomarkers of Essential Arterial Hypertension The Value of Prostacyclin, Nitric Oxide, Oxidized-LDL, and Peroxide Measurements

et al. 2009

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SummaryEndothelial function is impaired in hypertensive patients. Decreased nitric oxide and prostacyclin production as well as increased oxidative stress are involved in this abnormality.The aim of the present study was to evaluate whether biomarkers of endothelial dysfunction and oxidative stress have diagnostic value in patients with essential hypertension.We measured nitric oxide, prostacyclin, and oxidized-LDL levels and assessed oxidative status in 62 patients with diagnosed essential arterial hypertension and 45 healthy controls.In the hypertensive group, among measured parameters, the median prostacyclin level was significantly lower, when compared to healthy controls (125.57 pg/mL, 25%; 75% quartile range: 84.99; 275.93 and 462.9 pg/mL, 25%; 75% quartile range: 107.69; 849.3, respectively, P = 0.009). The largest area under the ROC curve was found for prostacyclin; 0.647 (95% C.I. 0.549 to 0.737). In the analysis of logistic regression, the prostacyclin and oxidized-LDL cut-off values were associated with a 4.9 higher significant risk of hypertension (O.R. 4.91 and 4.99, respectively; P = 0.0008 and P = 0.00065, respectively). Oxidized-LDL, a biomarker of endothelial damage, was the only one that had a significant negative correlation with protective prostacyclin in hypertensive patients (r = -0.29, P = 0.02).Of all the biomarkers prostacyclin and oxidized-LDL had the best diagnostic value for patients with hypertension. (Int Heart J 2009; 50: 341-351)

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Effect of N-acetyl-cysteine on the hypoxic ventilatory response and erythropoietin production: linkage between plasma thiol redox state and O2 chemosensitivity

Cited by 84 publications

References 32 publications

A Fenton reaction at the endoplasmic reticulum is involved in the redox control of hypoxia-inducible gene expression

A Fenton reaction at the endoplasmic reticulum is involved in the redox control of hypoxia-inducible gene expression

Effect of p47^phoxgene deletion on ROS production and oxygen sensing in mouse carotid body chemoreceptor cells

Diagnostic Biomarkers of Essential Arterial Hypertension The Value of Prostacyclin, Nitric Oxide, Oxidized-LDL, and Peroxide Measurements

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Effect of N-acetyl-cysteine on the hypoxic ventilatory response and erythropoietin production: linkage between plasma thiol redox state and O2 chemosensitivity

Cited by 84 publications

References 32 publications

A Fenton reaction at the endoplasmic reticulum is involved in the redox control of hypoxia-inducible gene expression

A Fenton reaction at the endoplasmic reticulum is involved in the redox control of hypoxia-inducible gene expression

Effect of p47phoxgene deletion on ROS production and oxygen sensing in mouse carotid body chemoreceptor cells

Diagnostic Biomarkers of Essential Arterial Hypertension The Value of Prostacyclin, Nitric Oxide, Oxidized-LDL, and Peroxide Measurements

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Effect of p47^phoxgene deletion on ROS production and oxygen sensing in mouse carotid body chemoreceptor cells