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Open AccessArticle

Thrombin Induces Angiotensin II-Mediated Senescence in Atrial Endothelial Cells: Impact on Pro-Remodeling Patterns

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INSERM UMR1260 Regenerative NanoMedicine, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Faculté de Pharmacie, BP 60024 FR-67401 Strasbourg, France
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Pôle d’Activité Médico-Chirurgicale Cardio-Vasculaire, Nouvel Hôpital Civil, Centre Hospitalier Universitaire, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, BP 426-67091 France
*
Authors to whom correspondence should be addressed.
J. Clin. Med. 2019, 8(10), 1570; https://doi.org/10.3390/jcm8101570
Received: 29 August 2019 / Revised: 16 September 2019 / Accepted: 25 September 2019 / Published: 1 October 2019
(This article belongs to the Section Vascular Medicine)
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. View Full-Text
Keywords: senescence; thrombin; atrial fibrillation; endothelium; angiotensin II; remodeling senescence; thrombin; atrial fibrillation; endothelium; angiotensin II; remodeling
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MDPI and ACS Style

Hasan, H.; Park, S.-H.; Auger, C.; Belcastro, E.; Matsushita, K.; Marchandot, B.; Lee, H.-H.; Qureshi, A.W.; Kauffenstein, G.; Ohlmann, P.; Schini-Kerth, V.B; Jesel, L.; Morel, O. Thrombin Induces Angiotensin II-Mediated Senescence in Atrial Endothelial Cells: Impact on Pro-Remodeling Patterns. J. Clin. Med. 2019, 8, 1570. https://doi.org/10.3390/jcm8101570

AMA Style

Hasan H, Park S-H, Auger C, Belcastro E, Matsushita K, Marchandot B, Lee H-H, Qureshi AW, Kauffenstein G, Ohlmann P, Schini-Kerth VB, Jesel L, Morel O. Thrombin Induces Angiotensin II-Mediated Senescence in Atrial Endothelial Cells: Impact on Pro-Remodeling Patterns. Journal of Clinical Medicine. 2019; 8(10):1570. https://doi.org/10.3390/jcm8101570

Chicago/Turabian Style

Hasan, Hira; Park, Sin-Hee; Auger, Cyril; Belcastro, Eugenia; Matsushita, Kensuke; Marchandot, Benjamin; Lee, Hyun-Ho; Qureshi, Abdul W.; Kauffenstein, Gilles; Ohlmann, Patrick; Schini-Kerth, Valérie B; Jesel, Laurence; Morel, Olivier. 2019. "Thrombin Induces Angiotensin II-Mediated Senescence in Atrial Endothelial Cells: Impact on Pro-Remodeling Patterns" J. Clin. Med. 8, no. 10: 1570. https://doi.org/10.3390/jcm8101570

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