Cargando…

Vascular Dysfunction in Experimental Diabetes Is Improved by Pentaerithrityl Tetranitrate but Not Isosorbide-5-Mononitrate Therapy

OBJECTIVE: Diabetes is associated with vascular oxidative stress, activation of NADPH oxidase, and uncoupling of nitric oxide (NO) synthase (endothelial NO synthase [eNOS]). Pentaerithrityl tetranitrate (PETN) is an organic nitrate with potent antioxidant properties via induction of heme oxygenase-1...

Descripción completa

Detalles Bibliográficos
Autores principales: Schuhmacher, Swenja, Oelze, Matthias, Bollmann, Franziska, Kleinert, Hartmut, Otto, Christian, Heeren, Tjebo, Steven, Sebastian, Hausding, Michael, Knorr, Maike, Pautz, Andrea, Reifenberg, Kurt, Schulz, Eberhard, Gori, Tommaso, Wenzel, Philip, Münzel, Thomas, Daiber, Andreas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178293/
https://www.ncbi.nlm.nih.gov/pubmed/21844097
http://dx.doi.org/10.2337/db10-1395
_version_ 1782212380666626048
author Schuhmacher, Swenja
Oelze, Matthias
Bollmann, Franziska
Kleinert, Hartmut
Otto, Christian
Heeren, Tjebo
Steven, Sebastian
Hausding, Michael
Knorr, Maike
Pautz, Andrea
Reifenberg, Kurt
Schulz, Eberhard
Gori, Tommaso
Wenzel, Philip
Münzel, Thomas
Daiber, Andreas
author_facet Schuhmacher, Swenja
Oelze, Matthias
Bollmann, Franziska
Kleinert, Hartmut
Otto, Christian
Heeren, Tjebo
Steven, Sebastian
Hausding, Michael
Knorr, Maike
Pautz, Andrea
Reifenberg, Kurt
Schulz, Eberhard
Gori, Tommaso
Wenzel, Philip
Münzel, Thomas
Daiber, Andreas
author_sort Schuhmacher, Swenja
collection PubMed
description OBJECTIVE: Diabetes is associated with vascular oxidative stress, activation of NADPH oxidase, and uncoupling of nitric oxide (NO) synthase (endothelial NO synthase [eNOS]). Pentaerithrityl tetranitrate (PETN) is an organic nitrate with potent antioxidant properties via induction of heme oxygenase-1 (HO-1). We tested whether treatment with PETN improves vascular dysfunction in the setting of experimental diabetes. RESEARCH DESIGN AND METHODS: After induction of hyperglycemia by streptozotocin (STZ) injection (60 mg/kg i.v.), PETN (15 mg/kg/day p.o.) or isosorbide-5-mononitrate (ISMN; 75 mg/kg/day p.o.) was fed to Wistar rats for 7 weeks. Oxidative stress was assessed by optical methods and oxidative protein modifications, vascular function was determined by isometric tension recordings, protein expression was measured by Western blotting, RNA expression was assessed by quantitative RT-PCR, and HO-1 promoter activity in stable transfected cells was determined by luciferase assays. RESULTS: PETN, but not ISMN, improved endothelial dysfunction. NADPH oxidase and serum xanthine oxidase activities were significantly reduced by PETN but not by ISMN. Both organic nitrates had minor effects on the expression of NADPH oxidase subunits, eNOS and dihydrofolate reductase (Western blotting). PETN, but not ISMN, normalized the expression of GTP cyclohydrolase-1, extracellular superoxide dismutase, and S-glutathionylation of eNOS, thereby preventing eNOS uncoupling. The expression of the antioxidant enzyme, HO-1, was increased by STZ treatment and further upregulated by PETN, but not ISMN, via activation of the transcription factor NRF2. CONCLUSIONS: In contrast to ISMN, the organic nitrate, PETN, improves endothelial dysfunction in diabetes by preventing eNOS uncoupling and NADPH oxidase activation, thereby reducing oxidative stress. Thus, PETN therapy may be suited to treat patients with cardiovascular complications of diabetes.
format Online
Article
Text
id pubmed-3178293
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher American Diabetes Association
record_format MEDLINE/PubMed
spelling pubmed-31782932012-10-01 Vascular Dysfunction in Experimental Diabetes Is Improved by Pentaerithrityl Tetranitrate but Not Isosorbide-5-Mononitrate Therapy Schuhmacher, Swenja Oelze, Matthias Bollmann, Franziska Kleinert, Hartmut Otto, Christian Heeren, Tjebo Steven, Sebastian Hausding, Michael Knorr, Maike Pautz, Andrea Reifenberg, Kurt Schulz, Eberhard Gori, Tommaso Wenzel, Philip Münzel, Thomas Daiber, Andreas Diabetes Pharmacology and Therapeutics OBJECTIVE: Diabetes is associated with vascular oxidative stress, activation of NADPH oxidase, and uncoupling of nitric oxide (NO) synthase (endothelial NO synthase [eNOS]). Pentaerithrityl tetranitrate (PETN) is an organic nitrate with potent antioxidant properties via induction of heme oxygenase-1 (HO-1). We tested whether treatment with PETN improves vascular dysfunction in the setting of experimental diabetes. RESEARCH DESIGN AND METHODS: After induction of hyperglycemia by streptozotocin (STZ) injection (60 mg/kg i.v.), PETN (15 mg/kg/day p.o.) or isosorbide-5-mononitrate (ISMN; 75 mg/kg/day p.o.) was fed to Wistar rats for 7 weeks. Oxidative stress was assessed by optical methods and oxidative protein modifications, vascular function was determined by isometric tension recordings, protein expression was measured by Western blotting, RNA expression was assessed by quantitative RT-PCR, and HO-1 promoter activity in stable transfected cells was determined by luciferase assays. RESULTS: PETN, but not ISMN, improved endothelial dysfunction. NADPH oxidase and serum xanthine oxidase activities were significantly reduced by PETN but not by ISMN. Both organic nitrates had minor effects on the expression of NADPH oxidase subunits, eNOS and dihydrofolate reductase (Western blotting). PETN, but not ISMN, normalized the expression of GTP cyclohydrolase-1, extracellular superoxide dismutase, and S-glutathionylation of eNOS, thereby preventing eNOS uncoupling. The expression of the antioxidant enzyme, HO-1, was increased by STZ treatment and further upregulated by PETN, but not ISMN, via activation of the transcription factor NRF2. CONCLUSIONS: In contrast to ISMN, the organic nitrate, PETN, improves endothelial dysfunction in diabetes by preventing eNOS uncoupling and NADPH oxidase activation, thereby reducing oxidative stress. Thus, PETN therapy may be suited to treat patients with cardiovascular complications of diabetes. American Diabetes Association 2011-10 2011-09-16 /pmc/articles/PMC3178293/ /pubmed/21844097 http://dx.doi.org/10.2337/db10-1395 Text en © 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Pharmacology and Therapeutics
Schuhmacher, Swenja
Oelze, Matthias
Bollmann, Franziska
Kleinert, Hartmut
Otto, Christian
Heeren, Tjebo
Steven, Sebastian
Hausding, Michael
Knorr, Maike
Pautz, Andrea
Reifenberg, Kurt
Schulz, Eberhard
Gori, Tommaso
Wenzel, Philip
Münzel, Thomas
Daiber, Andreas
Vascular Dysfunction in Experimental Diabetes Is Improved by Pentaerithrityl Tetranitrate but Not Isosorbide-5-Mononitrate Therapy
title Vascular Dysfunction in Experimental Diabetes Is Improved by Pentaerithrityl Tetranitrate but Not Isosorbide-5-Mononitrate Therapy
title_full Vascular Dysfunction in Experimental Diabetes Is Improved by Pentaerithrityl Tetranitrate but Not Isosorbide-5-Mononitrate Therapy
title_fullStr Vascular Dysfunction in Experimental Diabetes Is Improved by Pentaerithrityl Tetranitrate but Not Isosorbide-5-Mononitrate Therapy
title_full_unstemmed Vascular Dysfunction in Experimental Diabetes Is Improved by Pentaerithrityl Tetranitrate but Not Isosorbide-5-Mononitrate Therapy
title_short Vascular Dysfunction in Experimental Diabetes Is Improved by Pentaerithrityl Tetranitrate but Not Isosorbide-5-Mononitrate Therapy
title_sort vascular dysfunction in experimental diabetes is improved by pentaerithrityl tetranitrate but not isosorbide-5-mononitrate therapy
topic Pharmacology and Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178293/
https://www.ncbi.nlm.nih.gov/pubmed/21844097
http://dx.doi.org/10.2337/db10-1395
work_keys_str_mv AT schuhmacherswenja vasculardysfunctioninexperimentaldiabetesisimprovedbypentaerithrityltetranitratebutnotisosorbide5mononitratetherapy
AT oelzematthias vasculardysfunctioninexperimentaldiabetesisimprovedbypentaerithrityltetranitratebutnotisosorbide5mononitratetherapy
AT bollmannfranziska vasculardysfunctioninexperimentaldiabetesisimprovedbypentaerithrityltetranitratebutnotisosorbide5mononitratetherapy
AT kleinerthartmut vasculardysfunctioninexperimentaldiabetesisimprovedbypentaerithrityltetranitratebutnotisosorbide5mononitratetherapy
AT ottochristian vasculardysfunctioninexperimentaldiabetesisimprovedbypentaerithrityltetranitratebutnotisosorbide5mononitratetherapy
AT heerentjebo vasculardysfunctioninexperimentaldiabetesisimprovedbypentaerithrityltetranitratebutnotisosorbide5mononitratetherapy
AT stevensebastian vasculardysfunctioninexperimentaldiabetesisimprovedbypentaerithrityltetranitratebutnotisosorbide5mononitratetherapy
AT hausdingmichael vasculardysfunctioninexperimentaldiabetesisimprovedbypentaerithrityltetranitratebutnotisosorbide5mononitratetherapy
AT knorrmaike vasculardysfunctioninexperimentaldiabetesisimprovedbypentaerithrityltetranitratebutnotisosorbide5mononitratetherapy
AT pautzandrea vasculardysfunctioninexperimentaldiabetesisimprovedbypentaerithrityltetranitratebutnotisosorbide5mononitratetherapy
AT reifenbergkurt vasculardysfunctioninexperimentaldiabetesisimprovedbypentaerithrityltetranitratebutnotisosorbide5mononitratetherapy
AT schulzeberhard vasculardysfunctioninexperimentaldiabetesisimprovedbypentaerithrityltetranitratebutnotisosorbide5mononitratetherapy
AT goritommaso vasculardysfunctioninexperimentaldiabetesisimprovedbypentaerithrityltetranitratebutnotisosorbide5mononitratetherapy
AT wenzelphilip vasculardysfunctioninexperimentaldiabetesisimprovedbypentaerithrityltetranitratebutnotisosorbide5mononitratetherapy
AT munzelthomas vasculardysfunctioninexperimentaldiabetesisimprovedbypentaerithrityltetranitratebutnotisosorbide5mononitratetherapy
AT daiberandreas vasculardysfunctioninexperimentaldiabetesisimprovedbypentaerithrityltetranitratebutnotisosorbide5mononitratetherapy