Nitroglycerin induces DNA damage and vascular cell death in the setting of nitrate tolerance

Mikhed, Yuliya; Fahrer, Jörg; Oelze, Matthias; Kröller‐Schön, Swenja; Steven, Sebastian; Welschof, Philipp; Zinßius, Elena; Stamm, Paul; Kashani, F. Ravandi; Roohani, Siyer; Kress, Joana M.; Ullmann, Elisabeth; Tran, Lan; Schulz, Eberhard; Epe, Bernd; Kaina, Bernd; Münzel, Thomas; Daiber, Andreas

doi:10.1007/s00395-016-0571-4

Cited by 16 publications

(18 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…7 It has been reported that GTN therapy may cause nitrate tolerance through DNA damage, induction of microRNA-199, and endothelial dysfunction. [8][9][10] S-nitrosylation is a ubiquitous redox-related modification of cysteine thiol by NO, which transduces NO bioactivity. 11,12 Accumulating evidence suggests that S-nitrosylation, such as S-nitrosothiols, plays key roles in human health and diseases.…”

Section: Study Highlightsmentioning

confidence: 99%

See 1 more Smart Citation

S‐Nitrosylation of Prostacyclin Synthase Instigates Nitrate Cross‐Tolerance In Vivo

Zhou

Wang

et al. 2018

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

Development of nitrate tolerance is a major drawback to nitrate therapy. Prostacyclin (PGI2) is a powerful vasodilator produced from prostaglandin (PGH2) by prostacyclin synthase (PGIS) in endothelial cells. This study aimed to determine the role of PGIS S-nitrosylation in nitrate tolerance induced by nitroglycerin (GTN). In endothelial cells, GTN increased PGIS S-nitrosylation and disturbed PGH2 metabolism, which were normalized by mutants of PGIS cysteine 231/441 to alanine (C231/441A). Clearance of nitric oxide by carboxy-PTIO or inhibition of S-nitrosylation by N-acetyl-cysteine decreased GTN-induced PGIS S-nitrosylation. Enforced expression of mutated PGIS with C231/441A markedly abolished GTN-induced PGIS S-nitrosylation and nitrate cross-tolerance in Apoe mice. Inhibition of cyclooxygenase 1 by aspirin, supplementation of PGI2 by beraprost, and inhibition of PGIS S-nitrosylation by N-acetyl-cysteine improved GTN-induced nitrate cross-tolerance in rats. In patients, increased PGIS S-nitrosylation was associated with nitrate tolerance. In conclusion, GTN induces nitrate cross-tolerance through PGIS S-nitrosylation at cysteine 231/441.

show abstract

Section: Study Highlightsmentioning

confidence: 99%

“…It has been reported that GTN therapy may cause nitrate tolerance through DNA damage, induction of microRNA‐199, and endothelial dysfunction . S‐nitrosylation is a ubiquitous redox‐related modification of cysteine thiol by NO, which transduces NO bioactivity .…”

mentioning

confidence: 99%

S‐Nitrosylation of Prostacyclin Synthase Instigates Nitrate Cross‐Tolerance In Vivo

Zhou

Wang

et al. 2018

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

show abstract

“…The method of densitometric quantification of endothelial DHE staining was adopted from a published protocol [68](A-C) Stainings were selected from unused pictures and graphs were drafted de novo from original data published in Schuhmacher et al, Hypertension 2010 [23]. Aortic endothelial DHE staining correlated well with endothelial dysfunction measured by ACh-dependent relaxation using isometric tension recording [62] (D), impaired calcium ionophore-stimulated tolerance in rat [38], mouse [39], rabbits [40] and human [41]; isosorbide-5-mononitrate-induced endothelial dysfunction [26]; cyclooxygenase inhibitor-induced NADPH oxidase activation in rat [42]; atherosclerosis in Watanabe Heritable Hyperlipidemic (WHHL) rabbits [40,43], ApoE knockout [44] and high fat diet fed mice (Steven et al, in revision in Cardiovasc. Res.…”

Section: Dihydroethidium Oxidative Fluorescence Microtopography (Dhe mentioning

confidence: 99%

“…We employed the L-012 ECL assay for measuring mitochondrial peroxynitrite formation in nitrate tolerance induced by nitroglycerin in rats [39,[112][113][114][115][116][117] or mice [56,118,119]. In these publications L-012 ECL signals correlated well with 3-nitrotyrosine levels in mitochondria of various tissues upon in vitro and in vivo nitroglycerin treatment, with ROS and RNS detection by other assays such as HPLC-based 2-hydroxyethidium measurement or dihydrorhodamine fluorescence, inhibition of the redox-sensitive enzyme mitochondrial aldehyde dehydrogenase (ALDH-2) and other markers of oxidative stress such as products of lipid peroxidation or 8-oxo-G and was improved by various antioxidant therapies (reviewed in [120]).…”

Section: L-012-based Whole Blood Chemiluminescence Assay (L-012 Oxidamentioning

confidence: 99%

See 1 more Smart Citation

Taking up the cudgels for the traditional reactive oxygen and nitrogen species detection assays and their use in the cardiovascular system

Daiber

Oelze

Sebastian

et al. 2017

Free Radical Biology and Medicine

Self Cite

View full text Add to dashboard Cite

Keywords:Oxidative stress Redox signaling Fluorescence and chemiluminescence-based assays Dihydroethidium oxidative fluorescence microtopography Lucigenin-enhanced chemiluminescence L-012-enhanced chemiluminescence A B S T R A C T Reactive oxygen and nitrogen species (RONS such as H 2 O 2 , nitric oxide) confer redox regulation of essential cellular functions (e.g. differentiation, proliferation, migration, apoptosis), initiate and catalyze adaptive stress responses. In contrast, excessive formation of RONS caused by impaired break-down by cellular antioxidant systems and/or insufficient repair of the resulting oxidative damage of biomolecules may lead to appreciable impairment of cellular function and in the worst case to cell death, organ dysfunction and severe disease phenotypes of the entire organism. Therefore, the knowledge of the severity of oxidative stress and tissue specific localization is of great biological and clinical importance. However, at this level of investigation quantitative information may be enough. For the development of specific drugs, the cellular and subcellular localization of the sources of RONS or even the nature of the reactive species may be of great importance, and accordingly, more qualitative information is required. These two different philosophies currently compete with each other and their different needs (also reflected by different detection assays) often lead to controversial discussions within the redox research community. With the present review we want to shed some light on these different philosophies and needs (based on our personal views), but also to defend some of the traditional assays for the detection of RONS that work very well in our hands and to provide some guidelines how to use and interpret the results of these assays. We will also provide an overview on the "new assays" with a brief discussion on their strengths but also weaknesses and limitations.

show abstract

Immunological and mass spectrometry-based approaches to determine thresholds of the mutagenic DNA adduct O6-methylguanine in vivo

et al. 2018

Self Cite

View full text Add to dashboard Cite

N-nitroso compounds are alkylating agents, which occur widespread in diet and environment. They induce DNA alkylation adducts such as O 6-methylguanine (O 6-MeG), which is repaired by O 6-methylguanine-DNA methyltransferase (MGMT). Persistent O 6-MeG lesions have detrimental biological consequences like mutagenicity and cytotoxicity. Due to its pivotal role in the etiology of cancer and in cytotoxic cancer therapy, it is important to detect and quantify O 6-MeG in biological specimens in a sensitive and accurate manner. Here, we used immunological approaches and established an ultra-performance liquid chromatographytandem mass spectrometry (UPLC-MS/MS) to monitor O 6-MeG adducts. First, colorectal cancer (CRC) cells were treated with the methylating anticancer drug temozolomide (TMZ). Immunofluorescence microscopy and an immuno-slot blot assay, both based on an adductspecific antibody, allowed for the semi-quantitative, dose-dependent assessment of O 6-MeG in CRC cells. Using the highly sensitive and specific UPLC-MS/MS, TMZ-induced O 6-MeG adducts were quantified in CRC cells and even in peripheral blood mononuclear cells exposed to clinically relevant TMZ doses. Furthermore, all methodologies were used to detect O 6-MeG in wildtype (WT) and MGMT-deficient mice challenged with the carcinogen azoxymethane. UPLC-MS/MS measurements and dose-response modeling revealed a nonlinear formation of hepatic and colonic O 6-MeG adducts in WT, whereas linear O 6-MeG formation without a threshold was observed in MGMT-deficient mice. Collectively, the UPLC-MS/MS analysis is highly sensitive and specific for O 6-MeG, thereby allowing for the first time for the determination of thresholds upon exposure to O 6-methylating agents. We envision that this method will be instrumental to monitor the efficacy of methylating chemotherapy and to assess dietary exposures. MATERIAL AND METHODS Material All solutions were made with deionized water (18.2 MΩ resistivity). O 6-methyl-d3-guanine (O 6-Me-d3-G) was from Toronto Research Chemicals (Toronto, Canada). O 6-MeG, ammonium hydroxide (ACS Reagent 28-30 %), hydrochloric acid (ACS Reagent 37 %), and acetic acid (HPLC grade) were purchased from Sigma-Aldrich (Buchs, Switzerland). Guanine was obtained from Acros Organics (New Jersey, USA) and Strata-X polymeric columns (30 μm) were from Phenomenex (Torrance, USA). Methanol (HPLC Gradient Grade) was bought at VWR (Dietikon, Switzerland).

show abstract

Nitroglycerin induces DNA damage and vascular cell death in the setting of nitrate tolerance

Cited by 16 publications

References 64 publications

S‐Nitrosylation of Prostacyclin Synthase Instigates Nitrate Cross‐Tolerance In Vivo

S‐Nitrosylation of Prostacyclin Synthase Instigates Nitrate Cross‐Tolerance In Vivo

Taking up the cudgels for the traditional reactive oxygen and nitrogen species detection assays and their use in the cardiovascular system

Immunological and mass spectrometry-based approaches to determine thresholds of the mutagenic DNA adduct O6-methylguanine in vivo

Contact Info

Product

Resources

About