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

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Abstract

Nitroglycerin (GTN) and other organic nitrates are widely used vasodilators. Their side effects are development of nitrate tolerance and endothelial dysfunction. Given the potential of GTN to induce nitro-oxidative stress, we investigated the interaction between nitro-oxidative DNA damage and vascular dysfunction in experimental nitrate tolerance. Cultured endothelial hybridoma cells (EA.hy 926) and Wistar rats were treated with GTN (ex vivo: 10–1000 µM; in vivo: 10, 20 and 50 mg/kg/day for 3 days, s.c.). The level of DNA strand breaks, 8-oxoguanine and O 6-methylguanine DNA adducts was determined by Comet assay, dot blot and immunohistochemistry. Vascular function was determined by isometric tension recording. DNA adducts and strand breaks were induced by GTN in cells in vitro in a concentration-dependent manner. GTN in vivo administration leads to endothelial dysfunction, nitrate tolerance, aortic and cardiac oxidative stress, formation of DNA adducts, stabilization of p53 and apoptotic death of vascular cells in a dose-dependent fashion. Mice lacking O 6-methylguanine-DNA methyltransferase displayed more vascular O 6-methylguanine adducts and oxidative stress under GTN therapy than wild-type mice. Although we were not able to prove a causal role of DNA damage in the etiology of nitrate tolerance, the finding of GTN-induced DNA damage such as the mutagenic and toxic adduct O 6-methylguanine, and cell death supports the notion that GTN based therapy may provoke adverse side effects, including endothelial function. Further studies are warranted to clarify whether GTN pro-apoptotic effects are related to an impaired recovery of patients upon myocardial infarction.

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Abbreviations

ACh:

Acetylcholine

t-BOOH:

Tert-butyl hydroperoxide

DEA/NO:

Diethylamine NONOate

DHE:

Dihydroethidium

EPR:

Electron paramagnetic resonance spectroscopy

eNOS:

Endothelial ·NO synthase (type 3)

ECL:

Enhanced chemiluminescence

EtOH:

Ethanol

GTN:

Glyceryl trinitrate (nitroglycerin)

IHC:

Immuno-histochemistry

ISMN:

Isosorbide-5-mononitrate

L-012:

8-Amino-5-chloro-7-phenylpyrido[3,4-d]pyridazine-1,4-(2H,3H)dione sodium salt

MGMT:

O 6-methylguanine-DNA methyltransferase

·NO:

Nitric oxide

Hb-NO:

Nitrosyl-iron hemoglobin

3NT:

3-Nitrotyrosine

O 6-me-G:

O 6-methylguanine

8-oxo-G:

8-Oxoguanine

RONS:

Reactive oxygen and nitrogen species

SDS-Page:

Sodium dodecyl sulfate-polyacrylamide electrophoresis

O2 ·− :

Superoxide anion radical

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Acknowledgments

We are indebted to Angelica Karpi, Jessica Rudolph, Bettina Mros, Jörg Schreiner, Nicole Glas, Svenja Stroh, Anna Frumkina and Georg Nagel for their expert technical assistance.

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    Authors and Affiliations

    1. Center of Cardiology-Cardiology 1, Molecular Cardiology, University Medical Center of the Johannes Gutenberg University, Langenbeckstr. 1, 55101, Mainz, Germany

      Yuliya Mikhed, Matthias Oelze, Swenja Kröller-Schön, Sebastian Steven, Philipp Welschof, Elena Zinßius, Paul Stamm, Fatemeh Kashani, Siyer Roohani, Elisabeth Ullmann, Lan P. Tran, Eberhard Schulz, Thomas Münzel & Andreas Daiber

    2. Department of Toxicology, University Medical Center of the Johannes Gutenberg University, Obere Zahlbacher Str. 67, 55131, Mainz, Germany

      Jörg Fahrer, Joana Melanie Kress & Bernd Kaina

    3. Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128, Mainz, Germany

      Bernd Epe

    4. German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Langenbeckstr. 1, 55101, Mainz, Germany

      Thomas Münzel & Andreas Daiber

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    Corresponding author

    Correspondence to Andreas Daiber.

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    Sources of funding

    Yuliya Mikhed holds a stipend from the International PhD Program on the ‘‘Dynamics of Gene Regulation, Epigenetics and DNA Damage Response’’ from the Institute of Molecular Biology gGmbH, (Mainz, Germany) funded by the Boehringer Ingelheim Foundation. The study was supported by long-lasting funding from the Mainzer Herz Stiftung and the Center for Translational Vascular Biology at the University Medical Center Mainz.

    Conflict of interest

    The authors declare no competing interests.

    Ethical standards

    All animal treatments were in accordance with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the U.S. National Institutes of Health and approved by the Ethics Commission according to the German Law on the Protection of Animals (Landesunter- suchungsamt Rheinland-Pfalz, Koblenz, Germany: #23 177-07/G12-1-084).

    Additional information

    Y. Mikhed, J. Fahrer and M. Oelze contributed equally to this work and are joint first authors.

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    Mikhed, Y., Fahrer, J., Oelze, M. et al. Nitroglycerin induces DNA damage and vascular cell death in the setting of nitrate tolerance. Basic Res Cardiol 111, 52 (2016). https://doi.org/10.1007/s00395-016-0571-4

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    • DOI: https://doi.org/10.1007/s00395-016-0571-4

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