Journal article
Sirtuin1-regulated lysine acetylation of p66Shc governs diabetes-induced vascular oxidative stress and endothelial dysfunction
Proceedings of the National Academy of Sciences - PNAS, Vol.114(7), pp.1714-1719
02/14/2017
DOI: 10.1073/pnas.1614112114
PMCID: PMC5321021
PMID: 28137876
Abstract
The 66-kDa Src homology 2 domain-containing protein (p66Shc) is a master regulator of reactive oxygen species (ROS). It is expressed in many tissues where it contributes to organ dysfunction by promoting oxidative stress. In the vasculature, p66Shc-induced ROS engenders endothelial dysfunction. Here we show that p66Shc is a direct target of the Sirtuin1 lysine deacetylase (Sirt1), and Sirt1-regulated acetylation of p66Shc governs its capacity to induce ROS. Using diabetes as an oxidative stimulus, we demonstrate that p66Shc is acetylated under high glucose conditions and is deacetylated by Sirt1 on lysine 81. High glucose-stimulated lysine acetylation of p66Shc facilitates its phosphorylation on serine 36 and translocation to the mitochondria, where it promotes hydrogen peroxide production. Endothelium-specific transgenic and global knockin mice expressing p66Shc that is not acetylatable on lysine 81 are protected from diabetic oxidative stress and vascular endothelial dysfunction. These findings show that p66Shc is a target of Sirt1, uncover a unique Sirt1-regulated lysine acetylation-dependent mechanism that governs the oxidative function of p66Shc, and demonstrate the importance of p66Shc lysine acetylation in vascular oxidative stress and diabetic vascular pathophysiology.
Details
- Title: Subtitle
- Sirtuin1-regulated lysine acetylation of p66Shc governs diabetes-induced vascular oxidative stress and endothelial dysfunction
- Creators
- Santosh Kumar - University of IowaYoung-Rae Kim - University of IowaAjit Vikram - University of IowaAsma Naqvi - Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213.Qiuxia Li - University of IowaModar Kassan - University of IowaVikas Kumar - Boston UniversityMarkus M. Bachschmid - Boston UniversityJulia S. Jacobs - University of IowaAjay Kumar - Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213.Kaikobad Irani - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.114(7), pp.1714-1719
- DOI
- 10.1073/pnas.1614112114
- PMID
- 28137876
- PMCID
- PMC5321021
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- Natl Acad Sciences
- Number of pages
- 6
- Grant note
- University of Iowa Endowed Professorship in Cardiovascular Medicine I01BX002940 / Veterans Affairs; US Department of Veterans Affairs R01DK103750 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) 1I01BX002940 / US Department of Veterans Affairs T32 HL007344; T32 HL007121 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA T32HL007121 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
- Language
- English
- Date published
- 02/14/2017
- Academic Unit
- Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984312974802771
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