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      Keap1 governs ageing-induced protein aggregation in endothelial cells

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          Abstract

          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.

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          Highlights

          • Physiological and premature ageing facilitates aggregation of proteins in ECs.

          • Loss of proteostasis depends on Keap1-driven S-nitrosation in ageing ECs.

          • Keap1:Nrf2 ratio predominates Nrf2 transcriptional activity in proteostasis control.

          • Keap1 or SNO depletion, or rapamycin treatment restore proteostasis in ageing ECs.

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          Most cited references39

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          The proteostasis network and its decline in ageing

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            The role of protein clearance mechanisms in organismal ageing and age-related diseases.

            The ability to maintain a functional proteome, or proteostasis, declines during the ageing process. Damaged and misfolded proteins accumulate with age, impairing cell function and tissue homeostasis. The accumulation of damaged proteins contributes to multiple age-related diseases such as Alzheimer's, Parkinson's or Huntington's disease. Damaged proteins are degraded by the ubiquitin-proteasome system or through autophagy-lysosome, key components of the proteostasis network. Modulation of either proteasome activity or autophagic-lysosomal potential extends lifespan and protects organisms from symptoms associated with proteostasis disorders, suggesting that protein clearance mechanisms are directly linked to ageing and age-associated diseases.
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              mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review

              The mechanistic target of rapamycin (mTOR) network is an evolutionary conserved signaling hub that senses and integrates environmental and intracellular nutrient and growth factor signals to coordinate basic cellular and organismal responses such as cell growth, proliferation, apoptosis, and inflammation dependent on the individual cell and tissue. A growing list of evidence suggests that mTOR signaling influences longevity and aging. Inhibition of the mTOR complex 1 (mTORC1) with rapamycin is currently the only known pharmacological treatment that increases lifespan in all model organisms studied. This review discusses the potential mechanisms how mTOR signaling controls lifespan and influences aging-related processes such as cellular senescence, metabolism, and stem cell function. Understanding these processes might provide novel therapeutic approaches to influence longevity and aging-related diseases.
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                Author and article information

                Contributors
                Journal
                Redox Biol
                Redox Biol
                Redox Biology
                Elsevier
                2213-2317
                19 May 2020
                July 2020
                19 May 2020
                : 34
                : 101572
                Affiliations
                [a ]Department of Medical Biotechnology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, 30-387, Krakow, Poland
                [b ]Department of Physics of Nanostructures and Nanotechnology, Institute of Physics, Jagiellonian University, 30-387, Krakow, Poland
                [c ]Institute of Nuclear Physics, Polish Academy of Sciences, 31-342, Krakow, Poland
                [d ]Mass Spectrometry Laboratory, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106, Warsaw, Poland
                Author notes
                []Corresponding author. Department of Medical Biotechnology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland. anna.grochot-przeczek@ 123456uj.edu.pl
                Article
                S2213-2317(20)30166-X 101572
                10.1016/j.redox.2020.101572
                7327977
                32487458
                baf123b6-cbff-41a4-a5aa-5f08e59da782
                © 2020 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 31 January 2020
                : 7 April 2020
                : 10 May 2020
                Categories
                Articles from the Special Issue on Redox Signalling and Cardiovascular Disease; Edited by Christopher Kevil and Yabing Chen

                ageing,endothelial cells,keap1,nrf2,protein aggregates,s-nitrosation

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