title: 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.
authors.forename: Anne H-H
authors.initials: AH
authors.lastname: Tseng
authors.affiliation: §Institute of Medical Sciences, Tzu-Chi University, Hualien 97004, Taiwan.
authors.forename: Li-Hong
authors.initials: LH
authors.lastname: Wu
authors.affiliation: ‡Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Shyan-Shu
authors.initials: SS
authors.lastname: Shieh
authors.forename: Danny Ling
authors.initials: DL
authors.lastname: Wang
mesh_terms: D000107:Acetylation; D015687:Cell Hypoxia / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D056566:Sirtuin 3 / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C466093:SIRT3 protein, human; D056566:Sirtuin 3