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S-Phase Kinase-associated Protein-2 Rejuvenates Senescent Endothelial Progenitor Cells and Induces Angiogenesis in Vivo

Cell cycle slowdown or arrest is a prominent feature of cellular senescence. S-phase kinase-associated protein-2 (Skp2), an F-box subunit of SCF(Skp2) ubiquitin ligase, is a key regulator of G1/S transition. We investigated whether Skp2 plays a role in the regulation of endothelial progenitor cell (...

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Autores principales: Wang, Hsueh-Hsiao, Lee, Yi-Nan, Su, Cheng-Huang, Shu, Kuo-Tung, Liu, Wen-Ting, Hsieh, Chin-Ling, Yeh, Hung-I, Wu, Yih-Jer
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171137/
https://www.ncbi.nlm.nih.gov/pubmed/32313103
http://dx.doi.org/10.1038/s41598-020-63716-y
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author Wang, Hsueh-Hsiao
Lee, Yi-Nan
Su, Cheng-Huang
Shu, Kuo-Tung
Liu, Wen-Ting
Hsieh, Chin-Ling
Yeh, Hung-I
Wu, Yih-Jer
author_facet Wang, Hsueh-Hsiao
Lee, Yi-Nan
Su, Cheng-Huang
Shu, Kuo-Tung
Liu, Wen-Ting
Hsieh, Chin-Ling
Yeh, Hung-I
Wu, Yih-Jer
author_sort Wang, Hsueh-Hsiao
collection PubMed
description Cell cycle slowdown or arrest is a prominent feature of cellular senescence. S-phase kinase-associated protein-2 (Skp2), an F-box subunit of SCF(Skp2) ubiquitin ligase, is a key regulator of G1/S transition. We investigated whether Skp2 plays a role in the regulation of endothelial progenitor cell (EPC) senescence, which is closely associated with aging-related vasculopathy. Replication-induced senescent EPCs demonstrated more pronounced senescence markers and lower Skp2 levels in comparison with those of their younger counterparts. Depletion of Skp2 induced increases in senescence-associated β-galactosidase (SA-βGal) activity and a reduction of telomere length and generated a senescent bioenergetics profile, whereas adenoviral-mediated Skp2 expression reversed the relevant senescence. EPCs isolated from older rats displayed a reduced proliferation rate and increased SA-βGal activity, both of which were significantly reversed by Skp2 ectopic expression. In addition to reversing senescence, Skp2 also rescued the angiogenic activity of senescent EPCs in the ischemic hind limbs of nude mice. The results revealed that ectopic expression of Skp2 has the potential to rejuvenate senescent EPCs and rescue their angiogenic activity and thus may be pivotal in the development of novel strategies to manage aging-related vascular disease.
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spelling pubmed-71711372020-04-24 S-Phase Kinase-associated Protein-2 Rejuvenates Senescent Endothelial Progenitor Cells and Induces Angiogenesis in Vivo Wang, Hsueh-Hsiao Lee, Yi-Nan Su, Cheng-Huang Shu, Kuo-Tung Liu, Wen-Ting Hsieh, Chin-Ling Yeh, Hung-I Wu, Yih-Jer Sci Rep Article Cell cycle slowdown or arrest is a prominent feature of cellular senescence. S-phase kinase-associated protein-2 (Skp2), an F-box subunit of SCF(Skp2) ubiquitin ligase, is a key regulator of G1/S transition. We investigated whether Skp2 plays a role in the regulation of endothelial progenitor cell (EPC) senescence, which is closely associated with aging-related vasculopathy. Replication-induced senescent EPCs demonstrated more pronounced senescence markers and lower Skp2 levels in comparison with those of their younger counterparts. Depletion of Skp2 induced increases in senescence-associated β-galactosidase (SA-βGal) activity and a reduction of telomere length and generated a senescent bioenergetics profile, whereas adenoviral-mediated Skp2 expression reversed the relevant senescence. EPCs isolated from older rats displayed a reduced proliferation rate and increased SA-βGal activity, both of which were significantly reversed by Skp2 ectopic expression. In addition to reversing senescence, Skp2 also rescued the angiogenic activity of senescent EPCs in the ischemic hind limbs of nude mice. The results revealed that ectopic expression of Skp2 has the potential to rejuvenate senescent EPCs and rescue their angiogenic activity and thus may be pivotal in the development of novel strategies to manage aging-related vascular disease. Nature Publishing Group UK 2020-04-20 /pmc/articles/PMC7171137/ /pubmed/32313103 http://dx.doi.org/10.1038/s41598-020-63716-y Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Wang, Hsueh-Hsiao
Lee, Yi-Nan
Su, Cheng-Huang
Shu, Kuo-Tung
Liu, Wen-Ting
Hsieh, Chin-Ling
Yeh, Hung-I
Wu, Yih-Jer
S-Phase Kinase-associated Protein-2 Rejuvenates Senescent Endothelial Progenitor Cells and Induces Angiogenesis in Vivo
title S-Phase Kinase-associated Protein-2 Rejuvenates Senescent Endothelial Progenitor Cells and Induces Angiogenesis in Vivo
title_full S-Phase Kinase-associated Protein-2 Rejuvenates Senescent Endothelial Progenitor Cells and Induces Angiogenesis in Vivo
title_fullStr S-Phase Kinase-associated Protein-2 Rejuvenates Senescent Endothelial Progenitor Cells and Induces Angiogenesis in Vivo
title_full_unstemmed S-Phase Kinase-associated Protein-2 Rejuvenates Senescent Endothelial Progenitor Cells and Induces Angiogenesis in Vivo
title_short S-Phase Kinase-associated Protein-2 Rejuvenates Senescent Endothelial Progenitor Cells and Induces Angiogenesis in Vivo
title_sort s-phase kinase-associated protein-2 rejuvenates senescent endothelial progenitor cells and induces angiogenesis in vivo
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171137/
https://www.ncbi.nlm.nih.gov/pubmed/32313103
http://dx.doi.org/10.1038/s41598-020-63716-y
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