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Cardiovascular Protective Effect of Metformin and Telmisartan: Reduction of PARP1 Activity via the AMPK-PARP1 Cascade
Hyperglycemia and hypertension impair endothelial function in part through oxidative stress-activated poly (ADP-ribose) polymerase 1 (PARP1). Biguanides and angiotensin II receptor blockers (ARBs) such as metformin and telmisartan have a vascular protective effect. We used cultured vascular endothel...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795690/ https://www.ncbi.nlm.nih.gov/pubmed/26986624 http://dx.doi.org/10.1371/journal.pone.0151845 |
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author | Shang, Fenqing Zhang, Jiao Li, Zhao Zhang, Jin Yin, Yanjun Wang, Yaqiong Marin, Traci L. Gongol, Brendan Xiao, Han Zhang, You-yi Chen, Zhen Shyy, John Y-J Lei, Ting |
author_facet | Shang, Fenqing Zhang, Jiao Li, Zhao Zhang, Jin Yin, Yanjun Wang, Yaqiong Marin, Traci L. Gongol, Brendan Xiao, Han Zhang, You-yi Chen, Zhen Shyy, John Y-J Lei, Ting |
author_sort | Shang, Fenqing |
collection | PubMed |
description | Hyperglycemia and hypertension impair endothelial function in part through oxidative stress-activated poly (ADP-ribose) polymerase 1 (PARP1). Biguanides and angiotensin II receptor blockers (ARBs) such as metformin and telmisartan have a vascular protective effect. We used cultured vascular endothelial cells (ECs), diabetic and hypertensive rodent models, and AMPKα2-knockout mice to investigate whether metformin and telmisartan have a beneficial effect on the endothelium via AMP-activated protein kinase (AMPK) phosphorylation of PARP1 and thus inhibition of PARP1 activity. The results showed that metformin and telmisartan, but not glipizide and metoprolol, activated AMPK, which phosphorylated PARP1 Ser-177 in cultured ECs and the vascular wall of rodent models. Experiments using phosphorylated/de-phosphorylated PARP1 mutants show that AMPK phosphorylation of PARP1 leads to decreased PARP1 activity and attenuated protein poly(ADP-ribosyl)ation (PARylation), but increased endothelial nitric oxide synthase (eNOS) activity and silent mating type information regulation 2 homolog 1 (SIRT1) expression. Taken together, the data presented here suggest biguanides and ARBs have a beneficial effect on the vasculature by the cascade of AMPK phosphorylation of PARP1 to inhibit PARP1 activity and protein PARylation in ECs, thereby mitigating endothelial dysfunction. |
format | Online Article Text |
id | pubmed-4795690 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-47956902016-03-23 Cardiovascular Protective Effect of Metformin and Telmisartan: Reduction of PARP1 Activity via the AMPK-PARP1 Cascade Shang, Fenqing Zhang, Jiao Li, Zhao Zhang, Jin Yin, Yanjun Wang, Yaqiong Marin, Traci L. Gongol, Brendan Xiao, Han Zhang, You-yi Chen, Zhen Shyy, John Y-J Lei, Ting PLoS One Research Article Hyperglycemia and hypertension impair endothelial function in part through oxidative stress-activated poly (ADP-ribose) polymerase 1 (PARP1). Biguanides and angiotensin II receptor blockers (ARBs) such as metformin and telmisartan have a vascular protective effect. We used cultured vascular endothelial cells (ECs), diabetic and hypertensive rodent models, and AMPKα2-knockout mice to investigate whether metformin and telmisartan have a beneficial effect on the endothelium via AMP-activated protein kinase (AMPK) phosphorylation of PARP1 and thus inhibition of PARP1 activity. The results showed that metformin and telmisartan, but not glipizide and metoprolol, activated AMPK, which phosphorylated PARP1 Ser-177 in cultured ECs and the vascular wall of rodent models. Experiments using phosphorylated/de-phosphorylated PARP1 mutants show that AMPK phosphorylation of PARP1 leads to decreased PARP1 activity and attenuated protein poly(ADP-ribosyl)ation (PARylation), but increased endothelial nitric oxide synthase (eNOS) activity and silent mating type information regulation 2 homolog 1 (SIRT1) expression. Taken together, the data presented here suggest biguanides and ARBs have a beneficial effect on the vasculature by the cascade of AMPK phosphorylation of PARP1 to inhibit PARP1 activity and protein PARylation in ECs, thereby mitigating endothelial dysfunction. Public Library of Science 2016-03-17 /pmc/articles/PMC4795690/ /pubmed/26986624 http://dx.doi.org/10.1371/journal.pone.0151845 Text en © 2016 Shang 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 Shang, Fenqing Zhang, Jiao Li, Zhao Zhang, Jin Yin, Yanjun Wang, Yaqiong Marin, Traci L. Gongol, Brendan Xiao, Han Zhang, You-yi Chen, Zhen Shyy, John Y-J Lei, Ting Cardiovascular Protective Effect of Metformin and Telmisartan: Reduction of PARP1 Activity via the AMPK-PARP1 Cascade |
title | Cardiovascular Protective Effect of Metformin and Telmisartan: Reduction of PARP1 Activity via the AMPK-PARP1 Cascade |
title_full | Cardiovascular Protective Effect of Metformin and Telmisartan: Reduction of PARP1 Activity via the AMPK-PARP1 Cascade |
title_fullStr | Cardiovascular Protective Effect of Metformin and Telmisartan: Reduction of PARP1 Activity via the AMPK-PARP1 Cascade |
title_full_unstemmed | Cardiovascular Protective Effect of Metformin and Telmisartan: Reduction of PARP1 Activity via the AMPK-PARP1 Cascade |
title_short | Cardiovascular Protective Effect of Metformin and Telmisartan: Reduction of PARP1 Activity via the AMPK-PARP1 Cascade |
title_sort | cardiovascular protective effect of metformin and telmisartan: reduction of parp1 activity via the ampk-parp1 cascade |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795690/ https://www.ncbi.nlm.nih.gov/pubmed/26986624 http://dx.doi.org/10.1371/journal.pone.0151845 |
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