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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November 2014
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Research Article|
October 23 2014
SIRT3 interactions with FOXO3 acetylation, phosphorylation and ubiquitinylation mediate endothelial cell responses to hypoxia
Anne H.-H. Tseng;
Anne H.-H. Tseng
*Taiwan International Graduate Program, Molecular Medicine Program, Academia Sinica, Taipei 11529, Taiwan
†Institute of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei 11221, Taiwan
‡Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan
§Institute of Medical Sciences, Tzu-Chi University, Hualien 97004, Taiwan
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Li-Hong Wu;
Li-Hong Wu
§Institute of Medical Sciences, Tzu-Chi University, Hualien 97004, Taiwan
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Shyan-Shu Shieh;
Shyan-Shu Shieh
‡Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan
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Danny Ling Wang
Danny Ling Wang
1
‡Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan
§Institute of Medical Sciences, Tzu-Chi University, Hualien 97004, Taiwan
1To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
March 10 2014
Revision Received:
August 21 2014
Accepted:
August 27 2014
Accepted Manuscript online:
August 27 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 464 (1): 157–168.
Article history
Received:
March 10 2014
Revision Received:
August 21 2014
Accepted:
August 27 2014
Accepted Manuscript online:
August 27 2014
Citation
Anne H.-H. Tseng, Li-Hong Wu, Shyan-Shu Shieh, Danny Ling Wang; SIRT3 interactions with FOXO3 acetylation, phosphorylation and ubiquitinylation mediate endothelial cell responses to hypoxia. Biochem J 15 November 2014; 464 (1): 157–168. doi: https://doi.org/10.1042/BJ20140213
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