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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
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.
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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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