Nucleoporin93 limits Yap activity to prevent endothelial cell senescence
© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd..
As the innermost lining of the vasculature, endothelial cells (ECs) are constantly subjected to systemic inflammation and particularly vulnerable to aging. Endothelial health is hence vital to prevent age-related vascular disease. Healthy ECs rely on the proper localization of transcription factors via nuclear pore complexes (NPCs) to govern cellular behavior. Emerging studies report NPC degradation with natural aging, suggesting impaired nucleocytoplasmic transport in age-associated EC dysfunction. We herein identify nucleoporin93 (Nup93), a crucial structural NPC protein, as an indispensable player in vascular protection. Endothelial Nup93 protein levels are significantly reduced in the vasculature of aged mice, paralleling observations of Nup93 loss when using in vitro models of EC senescence. The loss of Nup93 in human ECs induces cell senescence and promotes the expression of inflammatory adhesion molecules, where restoring Nup93 protein in senescent ECs reverses features of endothelial aging. Mechanistically, we find that both senescence and loss of Nup93 impair endothelial NPC transport, leading to nuclear accumulation of Yap and downstream inflammation. Pharmacological studies indicate Yap hyperactivation as the primary consequence of senescence and Nup93 loss in ECs. Collectively, our findings indicate that the maintenance of endothelial Nup93 is a key determinant of EC health, where aging targets endothelial Nup93 levels to impair NPC function as a novel mechanism of EC senescence and vascular aging.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:23 |
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| Enthalten in: |
Aging cell - 23(2024), 4 vom: 01. Apr., Seite e14095 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Nguyen, Tung D [VerfasserIn] |
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| Links: |
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| Themen: |
Endothelial cell inflammation |
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| Anmerkungen: |
Date Completed 17.04.2024 Date Revised 25.04.2024 published: Print-Electronic UpdateOf: bioRxiv. 2023 Nov 14;:. - PMID 38014013 Citation Status MEDLINE |
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| doi: |
10.1111/acel.14095 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 520 | |a © 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. | ||
| 520 | |a As the innermost lining of the vasculature, endothelial cells (ECs) are constantly subjected to systemic inflammation and particularly vulnerable to aging. Endothelial health is hence vital to prevent age-related vascular disease. Healthy ECs rely on the proper localization of transcription factors via nuclear pore complexes (NPCs) to govern cellular behavior. Emerging studies report NPC degradation with natural aging, suggesting impaired nucleocytoplasmic transport in age-associated EC dysfunction. We herein identify nucleoporin93 (Nup93), a crucial structural NPC protein, as an indispensable player in vascular protection. Endothelial Nup93 protein levels are significantly reduced in the vasculature of aged mice, paralleling observations of Nup93 loss when using in vitro models of EC senescence. The loss of Nup93 in human ECs induces cell senescence and promotes the expression of inflammatory adhesion molecules, where restoring Nup93 protein in senescent ECs reverses features of endothelial aging. Mechanistically, we find that both senescence and loss of Nup93 impair endothelial NPC transport, leading to nuclear accumulation of Yap and downstream inflammation. Pharmacological studies indicate Yap hyperactivation as the primary consequence of senescence and Nup93 loss in ECs. Collectively, our findings indicate that the maintenance of endothelial Nup93 is a key determinant of EC health, where aging targets endothelial Nup93 levels to impair NPC function as a novel mechanism of EC senescence and vascular aging | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Yap | |
| 650 | 4 | |a endothelial cell inflammation | |
| 650 | 4 | |a endothelial cell senescence | |
| 650 | 4 | |a nuclear pore complex | |
| 650 | 4 | |a vascular aging | |
| 700 | 1 | |a Rao, Mihir K |e verfasserin |4 aut | |
| 700 | 1 | |a Dhyani, Shaiva P |e verfasserin |4 aut | |
| 700 | 1 | |a Banks, Justin M |e verfasserin |4 aut | |
| 700 | 1 | |a Winek, Michael A |e verfasserin |4 aut | |
| 700 | 1 | |a Michalkiewicz, Julia |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Monica Y |e verfasserin |4 aut | |
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