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Keap1 governs ageing-induced protein aggregation in endothelial cells
The breach of proteostasis, leading to the accumulation of protein aggregates, is a hallmark of ageing and age-associated disorders, up to now well-established in neurodegeneration. Few studies have addressed the issue of dysfunctional cell response to protein deposition also for the cardiovascular...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327977/ https://www.ncbi.nlm.nih.gov/pubmed/32487458 http://dx.doi.org/10.1016/j.redox.2020.101572 |
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author | Kopacz, Aleksandra Kloska, Damian Targosz-Korecka, Marta Zapotoczny, Bartłomiej Cysewski, Dominik Personnic, Nicolas Werner, Ewa Hajduk, Karolina Jozkowicz, Alicja Grochot-Przeczek, Anna |
author_facet | Kopacz, Aleksandra Kloska, Damian Targosz-Korecka, Marta Zapotoczny, Bartłomiej Cysewski, Dominik Personnic, Nicolas Werner, Ewa Hajduk, Karolina Jozkowicz, Alicja Grochot-Przeczek, Anna |
author_sort | Kopacz, Aleksandra |
collection | PubMed |
description | The breach of proteostasis, leading to the accumulation of protein aggregates, is a hallmark of ageing and age-associated disorders, up to now well-established in neurodegeneration. Few studies have addressed the issue of dysfunctional cell response to protein deposition also for the cardiovascular system. However, the molecular basis of proteostasis decline in vascular cells, as well as its relation to ageing, are not understood. Recent studies have indicated the associations of Nrf2 transcription factor, the critical modulator of cellular stress-response, with ageing and premature senescence. In this report, we outline the significance of protein aggregation in physiological and premature ageing of murine and human endothelial cells (ECs). Our study shows that aged donor-derived and prematurely senescent Nrf2-deficient primary human ECs, but not those overexpressing dominant-negative Nrf2, exhibit increased accumulation of protein aggregates. Such phenotype is also found in the aortas of aged mice and young Nrf2 tKO mice. Ageing-related loss of proteostasis in ECs depends on Keap1, well-known repressor of Nrf2, recently perceived as a key independent regulator of EC function and protein S-nitrosation (SNO). Deposition of protein aggregates in ECs is associated with impaired autophagy. It can be counteracted by Keap1 depletion, S-nitrosothiol reductant or rapamycin treatment. Our results show that Keap1:Nrf2 protein balance and Keap1-dependent SNO predominate Nrf2 transcriptional activity-driven mechanisms in governing proteostasis in ageing ECs. |
format | Online Article Text |
id | pubmed-7327977 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-73279772020-07-06 Keap1 governs ageing-induced protein aggregation in endothelial cells Kopacz, Aleksandra Kloska, Damian Targosz-Korecka, Marta Zapotoczny, Bartłomiej Cysewski, Dominik Personnic, Nicolas Werner, Ewa Hajduk, Karolina Jozkowicz, Alicja Grochot-Przeczek, Anna Redox Biol Articles from the Special Issue on Redox Signalling and Cardiovascular Disease; Edited by Christopher Kevil and Yabing Chen The breach of proteostasis, leading to the accumulation of protein aggregates, is a hallmark of ageing and age-associated disorders, up to now well-established in neurodegeneration. Few studies have addressed the issue of dysfunctional cell response to protein deposition also for the cardiovascular system. However, the molecular basis of proteostasis decline in vascular cells, as well as its relation to ageing, are not understood. Recent studies have indicated the associations of Nrf2 transcription factor, the critical modulator of cellular stress-response, with ageing and premature senescence. In this report, we outline the significance of protein aggregation in physiological and premature ageing of murine and human endothelial cells (ECs). Our study shows that aged donor-derived and prematurely senescent Nrf2-deficient primary human ECs, but not those overexpressing dominant-negative Nrf2, exhibit increased accumulation of protein aggregates. Such phenotype is also found in the aortas of aged mice and young Nrf2 tKO mice. Ageing-related loss of proteostasis in ECs depends on Keap1, well-known repressor of Nrf2, recently perceived as a key independent regulator of EC function and protein S-nitrosation (SNO). Deposition of protein aggregates in ECs is associated with impaired autophagy. It can be counteracted by Keap1 depletion, S-nitrosothiol reductant or rapamycin treatment. Our results show that Keap1:Nrf2 protein balance and Keap1-dependent SNO predominate Nrf2 transcriptional activity-driven mechanisms in governing proteostasis in ageing ECs. Elsevier 2020-05-19 /pmc/articles/PMC7327977/ /pubmed/32487458 http://dx.doi.org/10.1016/j.redox.2020.101572 Text en © 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Articles from the Special Issue on Redox Signalling and Cardiovascular Disease; Edited by Christopher Kevil and Yabing Chen Kopacz, Aleksandra Kloska, Damian Targosz-Korecka, Marta Zapotoczny, Bartłomiej Cysewski, Dominik Personnic, Nicolas Werner, Ewa Hajduk, Karolina Jozkowicz, Alicja Grochot-Przeczek, Anna Keap1 governs ageing-induced protein aggregation in endothelial cells |
title | Keap1 governs ageing-induced protein aggregation in endothelial cells |
title_full | Keap1 governs ageing-induced protein aggregation in endothelial cells |
title_fullStr | Keap1 governs ageing-induced protein aggregation in endothelial cells |
title_full_unstemmed | Keap1 governs ageing-induced protein aggregation in endothelial cells |
title_short | Keap1 governs ageing-induced protein aggregation in endothelial cells |
title_sort | keap1 governs ageing-induced protein aggregation in endothelial cells |
topic | Articles from the Special Issue on Redox Signalling and Cardiovascular Disease; Edited by Christopher Kevil and Yabing Chen |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327977/ https://www.ncbi.nlm.nih.gov/pubmed/32487458 http://dx.doi.org/10.1016/j.redox.2020.101572 |
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