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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
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.
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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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