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Poly (ADP-Ribose) Polymerase 1 Mediated Arginase II Activation Is Responsible for Oxidized LDL-Induced Endothelial Dysfunction
It is well known that arginase II leads to decreased synthesis of nitric oxide (NO) by competing with endothelial nitric oxide synthase (eNOS) for their same substrate L-arginine. However, the regulatory mechanisms of arginase II production remain unclear. In this study, we hypothesized that poly- (...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2018
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104189/ https://www.ncbi.nlm.nih.gov/pubmed/30158868 http://dx.doi.org/10.3389/fphar.2018.00882 |
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author | Wang, Qi Zhao, Tong Zhang, Wei Yu, Wenbin Liu, Bin Wang, Zhaoyang Qiao, Wen Lu, Qinghua Wang, Aihua Zhang, Mingxiang |
author_facet | Wang, Qi Zhao, Tong Zhang, Wei Yu, Wenbin Liu, Bin Wang, Zhaoyang Qiao, Wen Lu, Qinghua Wang, Aihua Zhang, Mingxiang |
author_sort | Wang, Qi |
collection | PubMed |
description | It is well known that arginase II leads to decreased synthesis of nitric oxide (NO) by competing with endothelial nitric oxide synthase (eNOS) for their same substrate L-arginine. However, the regulatory mechanisms of arginase II production remain unclear. In this study, we hypothesized that poly- (ADP-ribose) transferase/polymerase-1 (PARP-1) may be a critical factor responsible for ox-LDL (oxidized Low Density Lipoprotein)-enhanced arginase II activity. We used serial deletions within plasmid constructs and found that a core promoter region of arginase II was located at the element of -774 to -738 bp and PARP-1 was identified specifically binding to this region. Inhibition of PARP-1 markedly reduced the endogenous arginase II expression and enhanced eNOS and NO production. Similarly, ox-LDL-induced increase in arginase II production and eNOS and NO reduction was substantially abolished by PARP-1 inhibition both in vitro and in vivo. Significant decrease in arginase II expression and increase in eNOS expression and NO levels, as well as improved endothelial function were observed in PARP-1-/- mice. The underlying mechanisms of ox-LDL-induced changes of PARP-1 expression involved migration of phosphorylated ERK2 into nuclei and direct interaction with PARP-1 which dramatically enhanced PARP-1 production, followed by histone acetylation to activate arginase II transcription process. Our studies demonstrated for the first time that PARP-1 regulates basal transcription process and ox-LDL-induced up-regulation of arginase II. These results demonstrated that PARP-1 offers a promising therapeutic target for endothelial dysfunction and atherosclerosis. |
format | Online Article Text |
id | pubmed-6104189 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-61041892018-08-29 Poly (ADP-Ribose) Polymerase 1 Mediated Arginase II Activation Is Responsible for Oxidized LDL-Induced Endothelial Dysfunction Wang, Qi Zhao, Tong Zhang, Wei Yu, Wenbin Liu, Bin Wang, Zhaoyang Qiao, Wen Lu, Qinghua Wang, Aihua Zhang, Mingxiang Front Pharmacol Pharmacology It is well known that arginase II leads to decreased synthesis of nitric oxide (NO) by competing with endothelial nitric oxide synthase (eNOS) for their same substrate L-arginine. However, the regulatory mechanisms of arginase II production remain unclear. In this study, we hypothesized that poly- (ADP-ribose) transferase/polymerase-1 (PARP-1) may be a critical factor responsible for ox-LDL (oxidized Low Density Lipoprotein)-enhanced arginase II activity. We used serial deletions within plasmid constructs and found that a core promoter region of arginase II was located at the element of -774 to -738 bp and PARP-1 was identified specifically binding to this region. Inhibition of PARP-1 markedly reduced the endogenous arginase II expression and enhanced eNOS and NO production. Similarly, ox-LDL-induced increase in arginase II production and eNOS and NO reduction was substantially abolished by PARP-1 inhibition both in vitro and in vivo. Significant decrease in arginase II expression and increase in eNOS expression and NO levels, as well as improved endothelial function were observed in PARP-1-/- mice. The underlying mechanisms of ox-LDL-induced changes of PARP-1 expression involved migration of phosphorylated ERK2 into nuclei and direct interaction with PARP-1 which dramatically enhanced PARP-1 production, followed by histone acetylation to activate arginase II transcription process. Our studies demonstrated for the first time that PARP-1 regulates basal transcription process and ox-LDL-induced up-regulation of arginase II. These results demonstrated that PARP-1 offers a promising therapeutic target for endothelial dysfunction and atherosclerosis. Frontiers Media S.A. 2018-08-15 /pmc/articles/PMC6104189/ /pubmed/30158868 http://dx.doi.org/10.3389/fphar.2018.00882 Text en Copyright © 2018 Wang, Zhao, Zhang, Yu, Liu, Wang, Qiao, Lu, Wang and Zhang. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Wang, Qi Zhao, Tong Zhang, Wei Yu, Wenbin Liu, Bin Wang, Zhaoyang Qiao, Wen Lu, Qinghua Wang, Aihua Zhang, Mingxiang Poly (ADP-Ribose) Polymerase 1 Mediated Arginase II Activation Is Responsible for Oxidized LDL-Induced Endothelial Dysfunction |
title | Poly (ADP-Ribose) Polymerase 1 Mediated Arginase II Activation Is Responsible for Oxidized LDL-Induced Endothelial Dysfunction |
title_full | Poly (ADP-Ribose) Polymerase 1 Mediated Arginase II Activation Is Responsible for Oxidized LDL-Induced Endothelial Dysfunction |
title_fullStr | Poly (ADP-Ribose) Polymerase 1 Mediated Arginase II Activation Is Responsible for Oxidized LDL-Induced Endothelial Dysfunction |
title_full_unstemmed | Poly (ADP-Ribose) Polymerase 1 Mediated Arginase II Activation Is Responsible for Oxidized LDL-Induced Endothelial Dysfunction |
title_short | Poly (ADP-Ribose) Polymerase 1 Mediated Arginase II Activation Is Responsible for Oxidized LDL-Induced Endothelial Dysfunction |
title_sort | poly (adp-ribose) polymerase 1 mediated arginase ii activation is responsible for oxidized ldl-induced endothelial dysfunction |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104189/ https://www.ncbi.nlm.nih.gov/pubmed/30158868 http://dx.doi.org/10.3389/fphar.2018.00882 |
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