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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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2011
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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 |
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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 |
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