The Antioxidant Defense Protein Ferritin Is a Novel and Specific Target for Pentaerithrityl Tetranitrate in Endothelial Cells

Oberle, Stefanie; Schwartz, P.; Abate, Aida; Schröder, H.

doi:10.1006/bbrc.1999.0941

Cited by 67 publications

(38 citation statements)

References 32 publications

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“…Although isosorbide dinitrate, isosorbide-5-mononitrate, and GTN result in clinical tolerance after chronic treatment (Schulz et al, 2002;Sekiya et al, 2005;Thomas et al, 2007), treatment of experimental animals and humans with the organic nitrate PETN is devoid of tolerance development and preserves endothelial function (Jurt et al, 2001;Gori et al, 2003). In contrast to all other available organic nitrates, PETN and its metabolites induce the antioxidant defense protein HO-1, thus increasing the formation of the antioxidant molecule bilirubin and the signaling molecule carbon monoxide (Oberle et al, 1999(Oberle et al, , 2003Wenzel et al, 2007c). In addition, increased expression of HO-1 in response to PETN treatment also leads to a marked increase in the expression of ferritin via HO-1-dependent release of free iron from endogenous heme sources (Oberle et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Monitoring White Blood Cell Mitochondrial Aldehyde Dehydrogenase Activity: Implications for Nitrate Therapy in Humans

Wenzel

Schulz²,

Gori³

et al. 2009

The Journal of Pharmacology and Experimental Therapeutics

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Recent animal data suggest that reduced lipoic acid (LA) prevents oxidative inhibition of the nitrate bioactivating enzyme, the mitochondrial aldehyde dehydrogenase (ALDH-2), and that pentaerythritol tetranitrate (PETN) does not induce nitrate tolerance because of its intrinsic antioxidative properties, thereby preserving ALDH-2 activity. We sought to determine whether ALDH-2 activity in circulating white blood cells (WBCs) can be used to monitor nitrate tolerance and whether LA can prevent nitroglycerin tachyphylaxis in humans. Eight healthy male volunteers received, in randomized order, a single dose of glyceryl trinitrate (GTN; 0.8 mg), PETN (80 mg), or GTN plus LA (600 mg) orally. GTN (30 min) and PETN (120 min) administration lead to a comparable dilation of the brachial artery (15 Ϯ 1%). In contrast to PETN, acute GTN treatment resulted in a 60% decrease in WBC ALDH-2 activity (high-performance liquid chromatography), 30% reduction of nitrate bioactivation, and 25% decrease in serum antioxidant capacity (fluorescence assay), which all were prevented by pretreatment with LA. Mechanistic studies in rats identified oxidative stress, ALDH-2 inactivation, and vascular dysfunction as common features in acute and chronic nitrate tolerance. Treatment with GTN, but not PETN, acutely inhibits ALDH-2 activity and nitrate bioactivation in healthy volunteers. These effects were prevented by LA pretreatment, emphasizing the role of oxidative stress-triggered ALDH-2 dysfunction. Assessment of WBC ALDH-2 activity could be used as an easily accessible marker for the detection of nitroglycerin-induced tachyphylaxis in humans and may be of high clinical interest because recent data suggest that ALDH-2 activity correlates with protection from ischemic heart damage in infarct models.

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Section: Discussionmentioning

confidence: 99%

Monitoring White Blood Cell Mitochondrial Aldehyde Dehydrogenase Activity: Implications for Nitrate Therapy in Humans

Wenzel

Schulz²,

Gori³

et al. 2009

The Journal of Pharmacology and Experimental Therapeutics

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“…Incubation with the cyclic nucleotide dbcGMP also resulted in increased levels of ferritin mRNA transcripts relative to control values. The effect of cGMP on ferritin transcription has received little attention, although Oberle et al (1999) reported that both db-cGMP and 8-bromo cGMP had no effect on ferritin protein synthesis in porcine aortic endothelial cells. It is possible that cGMP induces or stabilizes ferritin transcripts through activation of protein kinase G (PKG).…”

Section: Discussionmentioning

confidence: 99%

Accumulation and translation of ferritin heavy chain transcripts following anoxia exposure in a marine invertebrate

Larade

Storey

2004

Journal of Experimental Biology

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SUMMARYDifferential screening of a Littorina littorea (the common periwinkle) cDNA library identified ferritin heavy chain as an anoxia-induced gene in hepatopancreas. Northern blots showed that ferritin heavy chain transcript levels were elevated twofold during anoxia exposure, although nuclear run-off assays demonstrated that ferritin heavy chain mRNAs were not transcriptionally upregulated during anoxia. Polysome analysis indicated that existing ferritin transcripts were actively translated during the anoxic period. This result was confirmed via western blotting, which demonstrated a twofold increase in ferritin heavy chain protein levels during anoxia, with a subsequent decrease to control levels during normoxic recovery. Organ culture experiments using hepatopancreas slices demonstrated a >50%increase in ferritin heavy chain transcript levels in vitro under conditions of anoxia and freezing, as well as after incubation with the second messenger cGMP. Taken together, these results suggest that ferritin heavy chain is actively regulated during anoxia exposure in the marine snail, L. littorea.

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“…107¡111 The observed shearinduced downregulation of the transferrin receptor and the upregulation of ferritin heavy and light chains may suppress oxidative stress-related endothelial apoptosis by scavenging iron radicals. 69,70,112,113 TG F b and its signaling pathway appear to abrogate apoptosis as well. TGF b1, Smad6, Smad8 and the immediate early gene SG K are signi cantly upregulated by LSS, and are known to inhibit apoptosis in some contexts while the potentially proapoptotic growth factor BMP4 is downregulated by LSS in vitro.…”

Section: Prolonged Lss Is An Anti-apoptotic Stimulusmentioning

confidence: 99%

“…An extensive list of genes with antioxidant properties, including NAD (P)H :menadione oxidoreductase, HMOX1, SOD1, SOD 2, cyclo-oxygenase 2 (COX2), NOS3, thioredoxin reductase, glutathione peroxidase, glutathione-Stransferase, g-glutamyl cysteine synthase, microsomal epoxide hydrolase, ferritin (heavy and light chains), glucose-6-phosphate dehydrogenase, cytochrome P450 1A1 and cytochrome P450 1B1, are upregulated by prolonged LSS. 52,66,67,69,70,109,111,113,132¡136 (F igure 3). Although it is unlikely that all of these gene products maintain this antioxidant phenotype, the overall breadth of this genetic response suggests that the endothelium is capable of mounting a potent antioxidant response.…”

Section: The Mitigation Of Oxidant Stress and In Ammation By Lssmentioning

confidence: 99%

Adaptation of the endothelium to fluid flow: in vitro analyses of gene expression and in vivo implications

Wasserman

Topper

2004

Vasc Med

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Biomechanical forces generated by blood ow play an important role in the pathogenesis of vascular disease. For example, regions exposed to non-uniform shear stresses develop early atherosclerotic lesions while areas exposed to uniform shear stresses are protected. A variety of in vitro ow apparatuses have been created to apply well-characterized ow patterns to endothelial cells in an effort to dissect the cellular and molecular pathways involved in these distinct processes. Recent advances in biotechnology have permitted large-scale transcriptional pro ling techniques to replace candidate gene screens and have allowed the genome-wide examination of biomechanical force-induced endothelial gene expression pro les. This review provides an overview of biomechanical force-induced modulation of endothelial phenotype. It examines the effect of sustained laminar shear stress (LSS), a type of uniform shear stress, on in vitro endothelial gene expression by synthesizing data from the early candidate gene and differential display polymerase chain reaction (PCR) approaches to the numerous, recent, high throughput functional genomic analyses. These studies demonstrate that prolonged LSS regulates the expression of only a small percentage ( 1¡5%) of endothelial genes, and this transcriptional pro le produces an endothelial phenotype that is quiescent, being protected from apoptosis, in ammation and oxidative stress. These observations provide a possible molecular mechanism for the strong correlation between patterns of blood ow and the occurrence of vascular pathologies, such as atherosclerosis, in vivo.

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The Antioxidant Defense Protein Ferritin Is a Novel and Specific Target for Pentaerithrityl Tetranitrate in Endothelial Cells

Cited by 67 publications

References 32 publications

Monitoring White Blood Cell Mitochondrial Aldehyde Dehydrogenase Activity: Implications for Nitrate Therapy in Humans

Monitoring White Blood Cell Mitochondrial Aldehyde Dehydrogenase Activity: Implications for Nitrate Therapy in Humans

Accumulation and translation of ferritin heavy chain transcripts following anoxia exposure in a marine invertebrate

Adaptation of the endothelium to fluid flow: in vitro analyses of gene expression and in vivo implications

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