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Thrombin Induces Angiotensin II-Mediated Senescence in Atrial Endothelial Cells: Impact on Pro-Remodeling Patterns
Background: Besides its well-known functions in hemostasis, thrombin plays a role in various non-hemostatic biological and pathophysiologic processes. We examined the potential of thrombin to promote premature atrial endothelial cells (ECs) senescence. Methods and Results: Primary ECs were isolated...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833093/ https://www.ncbi.nlm.nih.gov/pubmed/31581517 http://dx.doi.org/10.3390/jcm8101570 |
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author | Hasan, Hira Park, Sin-Hee Auger, Cyril Belcastro, Eugenia Matsushita, Kensuke Marchandot, Benjamin Lee, Hyun-Ho Qureshi, Abdul Wahid Kauffenstein, Gilles Ohlmann, Patrick Schini-Kerth, Valérie B Jesel, Laurence Morel, Olivier |
author_facet | Hasan, Hira Park, Sin-Hee Auger, Cyril Belcastro, Eugenia Matsushita, Kensuke Marchandot, Benjamin Lee, Hyun-Ho Qureshi, Abdul Wahid Kauffenstein, Gilles Ohlmann, Patrick Schini-Kerth, Valérie B Jesel, Laurence Morel, Olivier |
author_sort | Hasan, Hira |
collection | PubMed |
description | Background: Besides its well-known functions in hemostasis, thrombin plays a role in various non-hemostatic biological and pathophysiologic processes. We examined the potential of thrombin to promote premature atrial endothelial cells (ECs) senescence. Methods and Results: Primary ECs were isolated from porcine atrial tissue. Endothelial senescence was assessed by measuring beta-galactosidase (SA-β-gal) activity using flow cytometry, oxidative stress using the redox-sensitive probe dihydroethidium, protein level by Western blot, and matrix metalloproteinases (MMPs) activity using zymography. Atrial endothelial senescence was induced by thrombin at clinically relevant concentrations. Thrombin induced the up-regulation of p53, a key regulator in cellular senescence and of p21 and p16, two cyclin-dependent kinase inhibitors. Nicotinamide adenine dinucleotide phosphate NADPH oxidase, cyclooxygenases and the mitochondrial respiration complex contributed to oxidative stress and senescence. Enhanced expression levels of vascular cell adhesion molecule (VCAM)-1, tissue factor, transforming growth factor (TGF)-β and MMP-2 and 9 characterized the senescence-associated secretory phenotype of atrial ECs. In addition, the pro-senescence endothelial response to thrombin was associated with an overexpression of both angiotensin converting enzyme and AT1 receptors and was inhibited by perindoprilat and losartan. Conclusions: Thrombin promotes premature ageing and senescence of atrial ECs and may pave the way to deleterious remodeling of atrial tissue by a local up-regulation of the angiotensin system and by promoting pro-inflammatory, pro-thrombotic, pro-fibrotic and pro-remodeling responses. Hence, targeting thrombin and/or angiotensin systems may efficiently prevent atrial endothelial senescence. |
format | Online Article Text |
id | pubmed-6833093 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-68330932019-11-25 Thrombin Induces Angiotensin II-Mediated Senescence in Atrial Endothelial Cells: Impact on Pro-Remodeling Patterns Hasan, Hira Park, Sin-Hee Auger, Cyril Belcastro, Eugenia Matsushita, Kensuke Marchandot, Benjamin Lee, Hyun-Ho Qureshi, Abdul Wahid Kauffenstein, Gilles Ohlmann, Patrick Schini-Kerth, Valérie B Jesel, Laurence Morel, Olivier J Clin Med Article Background: Besides its well-known functions in hemostasis, thrombin plays a role in various non-hemostatic biological and pathophysiologic processes. We examined the potential of thrombin to promote premature atrial endothelial cells (ECs) senescence. Methods and Results: Primary ECs were isolated from porcine atrial tissue. Endothelial senescence was assessed by measuring beta-galactosidase (SA-β-gal) activity using flow cytometry, oxidative stress using the redox-sensitive probe dihydroethidium, protein level by Western blot, and matrix metalloproteinases (MMPs) activity using zymography. Atrial endothelial senescence was induced by thrombin at clinically relevant concentrations. Thrombin induced the up-regulation of p53, a key regulator in cellular senescence and of p21 and p16, two cyclin-dependent kinase inhibitors. Nicotinamide adenine dinucleotide phosphate NADPH oxidase, cyclooxygenases and the mitochondrial respiration complex contributed to oxidative stress and senescence. Enhanced expression levels of vascular cell adhesion molecule (VCAM)-1, tissue factor, transforming growth factor (TGF)-β and MMP-2 and 9 characterized the senescence-associated secretory phenotype of atrial ECs. In addition, the pro-senescence endothelial response to thrombin was associated with an overexpression of both angiotensin converting enzyme and AT1 receptors and was inhibited by perindoprilat and losartan. Conclusions: Thrombin promotes premature ageing and senescence of atrial ECs and may pave the way to deleterious remodeling of atrial tissue by a local up-regulation of the angiotensin system and by promoting pro-inflammatory, pro-thrombotic, pro-fibrotic and pro-remodeling responses. Hence, targeting thrombin and/or angiotensin systems may efficiently prevent atrial endothelial senescence. MDPI 2019-10-01 /pmc/articles/PMC6833093/ /pubmed/31581517 http://dx.doi.org/10.3390/jcm8101570 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Hasan, Hira Park, Sin-Hee Auger, Cyril Belcastro, Eugenia Matsushita, Kensuke Marchandot, Benjamin Lee, Hyun-Ho Qureshi, Abdul Wahid Kauffenstein, Gilles Ohlmann, Patrick Schini-Kerth, Valérie B Jesel, Laurence Morel, Olivier Thrombin Induces Angiotensin II-Mediated Senescence in Atrial Endothelial Cells: Impact on Pro-Remodeling Patterns |
title | Thrombin Induces Angiotensin II-Mediated Senescence in Atrial Endothelial Cells: Impact on Pro-Remodeling Patterns |
title_full | Thrombin Induces Angiotensin II-Mediated Senescence in Atrial Endothelial Cells: Impact on Pro-Remodeling Patterns |
title_fullStr | Thrombin Induces Angiotensin II-Mediated Senescence in Atrial Endothelial Cells: Impact on Pro-Remodeling Patterns |
title_full_unstemmed | Thrombin Induces Angiotensin II-Mediated Senescence in Atrial Endothelial Cells: Impact on Pro-Remodeling Patterns |
title_short | Thrombin Induces Angiotensin II-Mediated Senescence in Atrial Endothelial Cells: Impact on Pro-Remodeling Patterns |
title_sort | thrombin induces angiotensin ii-mediated senescence in atrial endothelial cells: impact on pro-remodeling patterns |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833093/ https://www.ncbi.nlm.nih.gov/pubmed/31581517 http://dx.doi.org/10.3390/jcm8101570 |
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