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Pyrrolidine dithiocarbamate ameliorates endothelial dysfunction in thoracic aorta of diabetic rats by preserving vascular DDAH activity

OBJECTIVE: Endothelial dysfunction plays a pivotal role in the development of diabetic cardiovascular complications. Accumulation of endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) and inhibition of dimethylarginine dimethylaminohydrolase (DDAH) activity have been...

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Autores principales: Lu, Chang-Wu, Lin, Yuan, Lei, Yan-Ping, Wang, Lan, He, Zhi-Min, Xiong, Yan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513417/
https://www.ncbi.nlm.nih.gov/pubmed/28715444
http://dx.doi.org/10.1371/journal.pone.0179908
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author Lu, Chang-Wu
Lin, Yuan
Lei, Yan-Ping
Wang, Lan
He, Zhi-Min
Xiong, Yan
author_facet Lu, Chang-Wu
Lin, Yuan
Lei, Yan-Ping
Wang, Lan
He, Zhi-Min
Xiong, Yan
author_sort Lu, Chang-Wu
collection PubMed
description OBJECTIVE: Endothelial dysfunction plays a pivotal role in the development of diabetic cardiovascular complications. Accumulation of endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) and inhibition of dimethylarginine dimethylaminohydrolase (DDAH) activity have been involved in diabetic endothelial dysfunction. This study was to investigate the effect of pyrrolidine dithiocarbamate (PDTC) on impairment of endothelium-dependent vasodilatation in diabetic rats and its potential mechanism. METHODS: Diabetic rats were induced by a single intraperitoneal injection of streptozotocin (60mg/kg), and PDTC (10mg/kg) was given in drinking water for 8 weeks. Blood glucose and serum ADMA concentrations were measured in experimental rats. Recombinant adenovirus encoding human DDAH2 gene were constructed and ex vivo transferred to isolated rat aortas. The maximal relaxation (E(max)) and half maximal effective concentration (EC(50)) of aortic rings response to accumulative concentrations of acetylcholine and vascular DDAH activity were examined before and after gene transfection. RESULTS: Diabetic rats displayed significant elevations of blood glucose and serum ADMA levels compared to control group (P<0.01). Vascular DDAH activity and endothelium-dependent relaxation of aortas were inhibited, as expressed by the decreased E(max) and increased EC(50) in diabetic rats compared to control rats (P<0.01). Treatment with PDTC not only decreased blood glucose and serum ADMA concentration (P<0.01) but also restored vascular DDAH activity and endothelium-dependent relaxation, evidenced by the higher E(max) and lower EC(50) in PDTC-treated diabetic rats compared to untreated diabetic rats (P<0.01). Similar restoration of E(max), EC(50) and DDAH activity were observed in diabetic aortas after DDAH2-gene transfection. CONCLUSIONS: These results indicate that PDTC could ameliorate impairment of endothelium-dependent relaxation in diabetic rats. The underlying mechanisms might be related to preservation of vascular DDAH activity and consequent reduction of endogenous ADMA in endothelium via its antioxidant action. This study highlights the therapeutic potential of PDTC in impaired vasodilation and provides a new strategy for treatment of diabetic cardiovascular complications.
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spelling pubmed-55134172017-08-07 Pyrrolidine dithiocarbamate ameliorates endothelial dysfunction in thoracic aorta of diabetic rats by preserving vascular DDAH activity Lu, Chang-Wu Lin, Yuan Lei, Yan-Ping Wang, Lan He, Zhi-Min Xiong, Yan PLoS One Research Article OBJECTIVE: Endothelial dysfunction plays a pivotal role in the development of diabetic cardiovascular complications. Accumulation of endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) and inhibition of dimethylarginine dimethylaminohydrolase (DDAH) activity have been involved in diabetic endothelial dysfunction. This study was to investigate the effect of pyrrolidine dithiocarbamate (PDTC) on impairment of endothelium-dependent vasodilatation in diabetic rats and its potential mechanism. METHODS: Diabetic rats were induced by a single intraperitoneal injection of streptozotocin (60mg/kg), and PDTC (10mg/kg) was given in drinking water for 8 weeks. Blood glucose and serum ADMA concentrations were measured in experimental rats. Recombinant adenovirus encoding human DDAH2 gene were constructed and ex vivo transferred to isolated rat aortas. The maximal relaxation (E(max)) and half maximal effective concentration (EC(50)) of aortic rings response to accumulative concentrations of acetylcholine and vascular DDAH activity were examined before and after gene transfection. RESULTS: Diabetic rats displayed significant elevations of blood glucose and serum ADMA levels compared to control group (P<0.01). Vascular DDAH activity and endothelium-dependent relaxation of aortas were inhibited, as expressed by the decreased E(max) and increased EC(50) in diabetic rats compared to control rats (P<0.01). Treatment with PDTC not only decreased blood glucose and serum ADMA concentration (P<0.01) but also restored vascular DDAH activity and endothelium-dependent relaxation, evidenced by the higher E(max) and lower EC(50) in PDTC-treated diabetic rats compared to untreated diabetic rats (P<0.01). Similar restoration of E(max), EC(50) and DDAH activity were observed in diabetic aortas after DDAH2-gene transfection. CONCLUSIONS: These results indicate that PDTC could ameliorate impairment of endothelium-dependent relaxation in diabetic rats. The underlying mechanisms might be related to preservation of vascular DDAH activity and consequent reduction of endogenous ADMA in endothelium via its antioxidant action. This study highlights the therapeutic potential of PDTC in impaired vasodilation and provides a new strategy for treatment of diabetic cardiovascular complications. Public Library of Science 2017-07-17 /pmc/articles/PMC5513417/ /pubmed/28715444 http://dx.doi.org/10.1371/journal.pone.0179908 Text en © 2017 Lu et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Lu, Chang-Wu
Lin, Yuan
Lei, Yan-Ping
Wang, Lan
He, Zhi-Min
Xiong, Yan
Pyrrolidine dithiocarbamate ameliorates endothelial dysfunction in thoracic aorta of diabetic rats by preserving vascular DDAH activity
title Pyrrolidine dithiocarbamate ameliorates endothelial dysfunction in thoracic aorta of diabetic rats by preserving vascular DDAH activity
title_full Pyrrolidine dithiocarbamate ameliorates endothelial dysfunction in thoracic aorta of diabetic rats by preserving vascular DDAH activity
title_fullStr Pyrrolidine dithiocarbamate ameliorates endothelial dysfunction in thoracic aorta of diabetic rats by preserving vascular DDAH activity
title_full_unstemmed Pyrrolidine dithiocarbamate ameliorates endothelial dysfunction in thoracic aorta of diabetic rats by preserving vascular DDAH activity
title_short Pyrrolidine dithiocarbamate ameliorates endothelial dysfunction in thoracic aorta of diabetic rats by preserving vascular DDAH activity
title_sort pyrrolidine dithiocarbamate ameliorates endothelial dysfunction in thoracic aorta of diabetic rats by preserving vascular ddah activity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513417/
https://www.ncbi.nlm.nih.gov/pubmed/28715444
http://dx.doi.org/10.1371/journal.pone.0179908
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