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SIRT3 interactions with FOXO3 acetylation, phosphorylation and ubiquitinylation mediate endothelial cell responses to hypoxia
Abstract
The endothelial cells (ECs) that line the vascular lumen are exposed to a wide variety of environmental stresses, such as hypoxia. Maladaptation to stress in ECs is a key event in the development of cardiovascular disease. Sirtuin 3 (SIRT3) is an NAD+-dependent protein deacetylase that modulates various proteins to control mitochondrial function and metabolism. We found that hypoxia elicits an increase in SIRT3 mRNA and protein expression in ECs. Under the same hypoxic conditions, the forkhead box class O transcription factor FOXO3 is deacetylated by SIRT3. The SIRT3-mediated deacetylation of FOXO3 further reduces FOXO3 phosphorylation, ubiquitination and degradation, thereby stabilizing FOXO3 proteins. As a result, the level of FOXO3 protein is increased during hypoxia. Moreover, a set of FOXO3-dependent mitochondrial antioxidant enzymes, including manganese superoxide dismutase (MnSOD), peroxiredoxin 3 (Prx3), Prx5 and thioredoxin 2 (Trx2), are up-regulated in ECs to facilitate ROS detoxification in response to hypoxia. The SIRT3-mediated deacetylation of FOXO3 preserves mitochondrial bioenergetic function and increases cell survival under hypoxic conditions. These results indicate that SIRT3 stabilizes FOXO3 via deacetylation, which enhances the mitochondrial antioxidant defence system to increase the adaptive capacity of ECs during hypoxia. This finding provides a direction for ameliorating the development of cardiovascular diseases.
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“Specifically, SIRT3 directly binds and deacetylates SOD2, thereby increasing SOD2 activity and subsequently leading to a significant effect on mtROS homeostasis, which plays a key protective role in high glucose–,43 angiotensin II–,44 and hypoxia45‐induced endothelial dysfunction.”
From Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway (2017) · cites this paper as [45]
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Metadata
- Authors
- Tseng, A. H.-H., Wu, L.-H., Shieh, S.-S., & Wang, D. L.
- Affiliations
- Tzu Chi University (TW)
- Institute of Medical Sciences, Tzu-Chi University, Hualien 97004, Taiwan
- Institute of Biomedical Sciences, Academia Sinica (TW)
- ORCID
- Wang, Danny Ling
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2014-10-23
- Volume
- 464
- Issue
- 1
- Pages
- 157-168
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W1978900120
- Cited by
- 114
- References
- 52
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 9 · 2023: 19 · 2022: 9 · 2021: 12 · 2020: 11 · 2019: 11 · 2018: 7 · 2017: 6 · 2016: 8 · 2015: 11 · 2014: 1
- FWCI
- 4.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Council
- Academia Sinica
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Keywords
- SIRT3, FOXO3, hypoxia, endothelial cells, protein deacetylation, protein stability, ubiquitination, phosphorylation, mitochondrial antioxidant defense, reactive oxygen species, manganese superoxide dismutase, peroxiredoxin, thioredoxin 2, mitochondrial bioenergetics, cardiovascular disease
- MeSH terms
- Forkhead Box Protein O3, Acetylation, Cell Survival, Humans, Phosphorylation, Protein Binding, Cell Hypoxia, Endothelial Cells, Forkhead Transcription Factors, Ubiquitination, Sirtuin 3, Human Umbilical Vein Endothelial Cells
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